The DOI matches its Crossref record; 39 of the 41 references it cites were found in a registry or an index; 37 of the 55 sources its claims cite were checked for support.
Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib
Open accessPublished version of a preprint
Abstract
Purpose: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt signaling. Underlying biologic mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer. Experimental Design: The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1-mutation data (91 HCCs). Effects of sorafenib on Wnt signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model. Results: Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1 class (138 cases [21.5%]) or Wnt-TGFβ class (177 cases [27.6%]). CTNNB1 class was characterized by upregulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, whereas Wnt-TGFβ class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin. Sorafenib decreased Wnt signaling and β-catenin protein in HepG2 (CTNNB1 class), SNU387 (Wnt-TGFβ class), SNU398 (CTNNB1-mutation), and Huh7 (lithium-chloride-pathway activation) cell lines. In addition, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1 class–specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals. Conclusions: Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients. Sorafenib modulates β-catenin/Wnt signaling in experimental models that harbor the CTNNB1 class signature. Clin Cancer Res; 18(18); 4997–5007. ©2012 AACR.
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Written from the paper’s full text.
TL;DR
This study characterizes two distinct Wnt-activated hepatocellular carcinoma (HCC) molecular classes, CTNNB1 and Wnt-TGFβ, together accounting for 315/642 (49.1%) of analyzed HCCs. It further shows that sorafenib can suppress β-catenin/Wnt signaling in experimental liver cancer models, including CTNNB1-class-like HepG2 xenografts.
Key findings
- Among 642 HCC samples, 315 (49.1%) showed active Wnt signaling: 138 (21.5%) were CTNNB1-class and 177 (27.6%) were Wnt-TGFβ-class.
- CTNNB1-class was characterized by up-regulation of liver-related Wnt targets (7/9: GLUL, REG3A, LGR5, MERTK, TBX3, EPHB2, SPARCL1), nuclear/cytoplasmic β-catenin staining in 28/35 (80%) vs 18/108 (16.6%) non-Wnt HCCs, glutamine synthetase staining in 26/35 (74.3%) vs 23/108 (21.3%), and enrichment of a CTNNB1-mutation signature.
- Wnt-TGFβ-class showed dysregulation of classical Wnt targets (e.g., MMP7, PLAU, RUNX2, CDC2, CCND3), activating alterations in FZD7, FZD6, TCF4, FRAT2, and ARBB2, absence of nuclear β-catenin, and enrichment in non-HCV etiology (35% vs 17% HCV-related).
- Sorafenib decreased Wnt signaling and β-catenin protein in HepG2, SNU398, SNU387, and Huh7 cells; reduced GLUL, LGR5, and TBX3 expression; and in HepG2 xenografts reduced tumor volume and extended median survival from 22 days (control, n=7) to 34 days (treated, n=7).
Methods
- The study analyzed mRNA expression from 642 HCCs and 21 liver cancer cell lines, miRNA expression from 89 HCCs, immunohistochemistry from 108 HCCs, and CTNNB1-mutation data from 91 HCCs, using training, validation, and public datasets.
- Wnt-pathway assessment used 210 Wnt-related genes and 49 Wnt-related miRNAs, with nearest template prediction, Comparative Marker Selection, FDR<0.05, gene set enrichment analysis, and a generated CTNNB1-mutation signature.
- Experimental validation used four liver cancer cell lines with TCF/LEF luciferase reporter assays, western blot, immunocytofluorescence, and RT-PCR, plus subcutaneous HepG2 xenografts in BALB/c mice treated with sorafenib at 30 mg/kg/day.
Limitations
- The paper states that the mechanism by which sorafenib modulates Wnt signaling remains unclear, whether Wnt modulation contributes to sorafenib’s antitumoral benefit in patients is unknown, why Wnt-TGFβ-class lacks detectable protein-level activation is unresolved, and TCF4 isoform functions and miRNA functional relevance require further analysis.
- Evident from the text: no patient treatment-response data are presented, so the clinical relevance of sorafenib’s Wnt-modulating effect is not established.
- Evident from the text: the in vivo validation uses a small xenograft experiment (n=7 per group), and the main drug findings rely on cell lines and a HepG2 xenograft model rather than primary human tumors.
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Claims the paper makes
56 Own result · 19 Own interpretation · 12 Partly supported · 11 Supported · 6 No full text of the sources · 5 Own method · 1 Supported so far · 1 Mixed support · 1 Couldn’t confirm · accuracy not yet measured
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Although several molecular classes have been associated with Wnt-signaling in HCC (5, 6, 8) and the concept of liver-related and classical Wnt-signaling has been proposed (29), no detailed characterization of underlying mechanisms has been pursued yet.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Supportedcites [5] Boyault, 2007, Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets, Hepatology source
The Abstract identifies G5 and G6 as HCC subgroups strongly related to β-catenin mutations and Wnt-pathway activation. That supports the part of the citing sentence attached to this source’s citation. The statement that no detailed mechanistic characterization had yet been pursued is the citing authors’ subsequent, uncited framing, not a claim attributed to this source. (LLM, conf=0.90)
- Supportedcites [6] Chiang, 2008, Focal gains of VEGFA and molecular classification of hepatocellular carcinoma, Cancer Res source
The citation is attached to the statement that molecular classes have been associated with Wnt signaling, not to the citing authors’ subsequent statement about the lack of detailed mechanistic characterization. The Results section identifies a CTNNB1-associated HCC class enriched for mutations and nuclear localization indicative of altered canonical Wnt signaling. (LLM, conf=0.91)
- Disputedcites [8] Hoshida, 2009, Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma, Cancer Res sourceExperimental — accuracy not yet measured
The Results sections “Mechanisms of WNT activation in S1 tumors” and “TGF-beta-WNT interactions” explicitly investigate how WNT signaling is activated, including experiments on TGF-beta stimulation and beta-catenin localization. The Discussion says additional mechanistic studies are required, but that does not support the claim that no characterization had been pursued. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Partly supportedcites [29] Nejak-Bowen, 2011, Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad, Semin Cancer Biol sourceExperimental — accuracy not yet measured
In ‘Phenotype of β-catenin-active HCC’ (page unavailable), the review says important questions about different modes of β-catenin activation remain unanswered and calls for careful comparative analysis. But ‘Activation of Wnt signaling in HCC in patients’ describes several underlying mechanisms already reported. The claim that no detailed characterization has been pursued is therefore broader than the review supports. (LLM, conf=0.82)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The biological similarity of HCC tumors within CTNNB1-class was further strengthened by a significant overlap with our recently published miRNA-class A (7).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Introduction
What the sources say
- Supportedcites [7] Toffanin, 2011, MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a, Gastroenterology source
The Results section (page not specified) identifies miRNA cluster A and reports that it is enriched for the CTNNB1-class gene signature and β-catenin mutations. This supports the claimed biological overlap. (LLM, conf=0.90)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This subclass strongly overlapped with Bouyault’s Wnt-related G5-6 classes, which were also characterized by mutations in CTNNB1 and significant over-expression of liver-related Wnt-target-genes (5, 6).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Introduction
What the sources say
- Supportedcites [5] Boyault, 2007, Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets, Hepatology source
The section on Wnt-pathway activation in G5 and G6 reports CTNNB1 mutations in 70% and 100% of tumors, respectively, and significant over-expression of β-catenin target genes, including known targets in the liver. The overlap with the citing paper’s CTNNB1 subclass is the citing authors’ comparison, not a finding attributed to Boyault et al. (LLM, conf=0.92)
- Partly supportedcites [6] Chiang, 2008, Focal gains of VEGFA and molecular classification of hepatocellular carcinoma, Cancer Res sourceExperimental — accuracy not yet measured
The Results section (page not available) reports that the CTNNB1-associated class was enriched for CTNNB1 mutations and significantly overexpressed liver-specific marker genes. It also reports strong concordance between two of its classes and external classifiers, but our copy does not identify those predictions as Bouyault’s G5–G6 classes or establish a strong overlap specifically with them. (LLM, conf=0.84)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In parallel, we characterized the molecular subclass S1 (Wnt-TGFβ) related to TGFβ-activated Wnt-signaling through a meta-analysis of 603 HCC patients (8).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Introduction
What the sources say
- Supportedcites [8] Hoshida, 2009, Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma, Cancer Res source
The Discussion reports an analysis of nine HCC datasets totaling 603 patients that identified subclasses S1, S2, and S3. The Results characterize S1 by co-occurring TGF-beta and WNT activity and report experiments showing that TGF-beta enhances WNT activity in HCC cells. Page numbers are not available in our copy. (LLM, conf=0.93)
plaincorrelationaln = 603- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The ability of the signature to capture CTNNB1 mutated samples was validated in one HCC dataset (5).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Materials and Methods > Genomic profiling of Wnt-related mRNAs and miRNAs
What the sources say
- Supportedcites [5] Boyault, 2007, Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets, Hepatology source
In ‘Identification of a predictor of the 6-groups classification,’ the paper says its 16-gene signature was applied to an independent validation set of 63 HCC samples. Table 1 reports that the resulting G5–G6 classification was associated with CTNNB1 mutations in that set (P<10⁻⁵). The signature is a six-group classifier, rather than one designed solely to identify CTNNB1 mutations. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Specifically, CTNNB1-mutation-signature was validated in one dataset where CTNNB1 mutations were reported (5).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
What the sources say
- Partly supportedcites [5] Boyault, 2007, Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets, Hepatology sourceExperimental — accuracy not yet measured
The Results section says the association between the G5–G6 transcriptomic groups and CTNNB1 mutations was validated in a second, independent set of 63 tumors. The 'Identification of a predictor' section describes the signature as a 16-gene predictor of six HCC groups, however, not a CTNNB1-mutation-specific signature. (LLM, conf=0.82)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Huh7 and SNU387 have no known mutations in β-catenin or other Wnt-related gens (27, 28).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Sorafenib alters Wnt-signaling in vitro and in vivo
What the sources say
- Partly supportedcites [27] Yuzugullu, 2009, Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells, Mol Cancer sourceExperimental — accuracy not yet measured
The Results (Figure 8b; page unavailable) place Huh7 among cell lines with wild-type β-catenin and Axin-1 genes. The paper also includes SNU387, but the retrieved passages do not explicitly establish its mutation status, and they do not establish that either line lacks mutations in all other Wnt-related genes. (LLM, conf=0.76)
- Partly supportedcites [28] Cagatay, 2002, P53 mutation as a source of aberrant beta-catenin accumulation in cancer cells, Oncogene sourceExperimental — accuracy not yet measured
The Comparative analysis section reports wild-type β-catenin in both Huh7 and SNU387. The Discussion reports no Axin1 mutation in Huh7 and says none was identified in the remaining nine cell lines, which includes SNU387. The paper does not establish the absence of mutations in all other Wnt-related genes in these two lines. (LLM, conf=0.85)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Both have been identified as distinct classes in several independent HCC datasets (8), underscoring their biological divergence.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Supportedcites [8] Hoshida, 2009, Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma, Cancer Res source
The Introduction reports three distinct HCC subclasses present in all nine datasets examined. The Results identify WNT/TGF-beta activity with S1 and place the previously reported CTNNB1 class within S3, supporting their identification as distinct classes across independent datasets. Page numbers are unavailable in our copy. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Our group recently reported two fundamentally different molecular classes associated to Wnt-signaling in HCC based on expression of liver-related (CTNNB1-class) or classical (Wnt-TGFβ-class) Wnt-target-genes (6, 8).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Partly supportedcites [6] Chiang, 2008, Focal gains of VEGFA and molecular classification of hepatocellular carcinoma, Cancer Res sourceExperimental — accuracy not yet measured
The Results section (page not provided) identifies a CTNNB1-associated HCC class with canonical Wnt-signaling alterations and overexpression of liver-specific marker genes. It does not report a second Wnt–TGFβ class defined by classical Wnt-target genes; the other classes it describes include proliferation and interferon-related classes. (LLM, conf=0.88)
- Partly supportedcites [8] Hoshida, 2009, Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma, Cancer Res sourceExperimental — accuracy not yet measured
In Results (‘Mechanisms of WNT activation in S1 tumors’; page unavailable), the paper distinguishes the S1 WNT signature, characterized by canonical targets such as cyclin D1 and MYC, from the previously reported CTNNB1 class, a subset of S3. It also finds WNT–TGFβ activity in S1. Our copy does not establish that the CTNNB1 class is defined by expression of liver-related WNT target genes, and the paper reports three overall HCC subclasses rather than two. (LLM, conf=0.85)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This is the case of both FZD7(21) and TCF4(22) which upregulation has been previously described to activate Wnt signaling in the absence of β-catenin mutations.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [21] Merle, 2004, Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma, Gastroenterology source
- Partly supportedcites [22] Ravindranath, 2011, Wnt-beta-catenin-Tcf-4 signalling-modulated invasiveness is dependent on osteopontin expression in breast cancer, Br J Cancer sourceExperimental — accuracy not yet measured
The Results section (‘Tcf-4-induced OPN may be dependent on the competency of Wnt signalling’; page unavailable) reports that Tcf-4 overexpression activated a Wnt-signalling reporter in MCF10AT cells, supporting the TCF4 portion attributed to this paper. The paper says there is no evidence for specific mutations in the breast-cancer context, but it does not establish that the tested cells lacked β-catenin mutations. FZD7 is attached to a different citation in the citing sentence and is not assessed here. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 15
- It may state two separate claims as one. 31
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Aberrant activation of Wnt can also result from mutations in the β-catenin gene (CTNNB1), which is the second most frequent mutation observed in HCC after the p53 tumor suppressor (TP53) (5).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Introduction
What the sources say
- Partly supportedcites [5] Boyault, 2007, Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets, Hepatology sourceExperimental — accuracy not yet measured
The paper’s introductory discussion of HCC pathways says Wnt activation occurs mainly through CTNNB1 mutations, and the Results identify CTNNB1 and TP53 as frequent somatic mutations. Neither passage establishes that CTNNB1 is the second most frequent mutation in HCC after TP53. Page numbers are unavailable in our copy. (LLM, conf=0.87)
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Nonetheless, Wnt-signaling associated molecular classes have been reported by different investigators emphasizing the importance of Wnt-aberrations in liver cancer (5, 6).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Introduction
What the sources say
- Supportedcites [5] Boyault, 2007, Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets, Hepatology source
The Abstract identifies G5 and G6 as molecular subgroups strongly associated with β-catenin mutations and Wnt pathway activation. The Results section on Wnt activation reports CTNNB1 mutations in 70% of G5 and 100% of G6 tumors, supporting this paper's contribution to the cited statement. (LLM, conf=0.92)
- Supportedcites [6] Chiang, 2008, Focal gains of VEGFA and molecular classification of hepatocellular carcinoma, Cancer Res source
The Introduction reports that gene-expression studies have converged on molecular classes of hepatocellular carcinoma, including a class with Wnt-pathway activation. The Results identify a CTNNB1-associated class enriched for mutations and nuclear localization, supporting the importance of Wnt alterations in a subset of liver cancers. Page numbers are not provided in our copy. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Wnt-signaling was also reportedly activated in a hepatic stem-cell-like HCC class showing a close correlation with EpCAM expression and induction of known Wnt-target-genes BAMBI and DKK1(9, 10).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Introduction
What the sources say
- Supportedcites [9] Yamashita, 2008, EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma, Cancer Res source
The Discussion reports Wnt–β-catenin activation in hepatic stem-cell-like HCC and a close correlation between that signaling and EpCAM-positive HCC. The Gene signature of EpCAM+ HCC section identifies BAMBI and DKK1 as Wnt targets and reports significantly increased expression of both in EpCAM-positive tumors (Fig. 2C). (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [10] Yamashita, 2007, Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma, Cancer Res source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We recently reported a molecular classification of HCC, which includes a CTNNB1-class characterized by over-expression of liver-related Wnt-target-genes”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Introduction
What the sources say
- Supportedcites [6] Chiang, 2008, Focal gains of VEGFA and molecular classification of hepatocellular carcinoma, Cancer Res source
The Results section identifies a CTNNB1-associated HCC class enriched for exon 3 mutations and nuclear localization of β-catenin, with significant overexpression of liver-specific marker genes. This supports the attributed description of the class. No page number is provided in our copy. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“among which five of them (FZD7, FZD6, TCF4, FRAT2 and ARBB2) have been related to Wnt activation in cancer (20-25)”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
What the sources say
- Partly supportedcites [20] Bengochea, 2008, Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma, Br J Cancer sourceExperimental — accuracy not yet measured
The Abstract reports FZD7 and FZD6 upregulation in hepatocellular carcinoma associated with activation of potentially FZD-dependent pathways. The Discussion says FZD7 can activate canonical Wnt signaling but that the evidence for FZD6 is less clear. The paper does not establish activating alterations in TCF4, FRAT2, or ARBB2, so it does not support the full five-gene claim. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [21] Merle, 2004, Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma, Gastroenterology source
- Partly supportedcites [22] Ravindranath, 2011, Wnt-beta-catenin-Tcf-4 signalling-modulated invasiveness is dependent on osteopontin expression in breast cancer, Br J Cancer sourceExperimental — accuracy not yet measured
The Conclusion section links Tcf-4 to Wnt signalling in breast cancer, supporting the TCF4 portion of the claim. It does not identify five activating alterations or link FZD7, FZD6, FRAT2, or ARBB2 to Wnt activation; it says there is no evidence for specific mutations in this context. (LLM, conf=0.84)
- Partly supportedcites [23] Bonnans, 2012, Essential requirement for beta-arrestin2 in mouse intestinal tumors with elevated Wnt signaling, Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
The Results report that Arrb2 knockdown reduced Wnt/β-catenin activity in a human colorectal cancer cell line with elevated Wnt signaling, supporting a link between ARRB2 and Wnt activity in cancer. The paper does not identify an activating alteration in ARRB2; it attributes the elevated signaling in those cells to APC inactivation. It also does not establish the claim for the other four listed genes. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [24] Saitoh, 2001, FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are upregulated in gastric cancer, Int J Oncol source
- Not checked — no full text of the sourcecites [25] Saitoh, 2001, Molecular cloning and characterization of FRAT2, encoding a positive regulator of the WNT signaling pathway, Biochem Biophys Res Commun source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Sorafenib was effective in modulating transcriptional activity through TCF site, and in decreasing β-catenin protein levels in cells with truncated/mutated β-catenin (HepG2, SNU398), in cells with wild type β-catenin (SNU387) and in cells with wild type β-catenin and induction of Wnt-signaling by GSK3β-inhibitor LiCl (Huh7) (Fig. 4A, Suppl. Fig. 7) (16).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Sorafenib alters Wnt-signaling in vitro and in vivo
What the sources say
- Supportedcites [16] Stambolic, 1996, Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells, Curr Biol source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: HepG2 cells express a truncated β-catenin lacking the Ser/Thr domain that regulates its degradation, and SNU398 cells have a point mutation in a key Ser in the same domain (S37C).
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While the CTNNB1-class was correlated with CTNNB1-mutations, nuclear β-catenin staining and tumor diameter >3cm (6), Wnt-TGFβ-class was associated with TGF-β activation, cytoplasmic β-catenin staining, vascular invasion, satellitosis and greater risk of early recurrence after surgical resection (8).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Supportedcites [8] Hoshida, 2009, Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma, Cancer Res source
The Results sections on WNT activation and TGF-beta–WNT interactions identify S1 as the subclass with TGF-beta/WNT activity and elevated cytoplasmic beta-catenin staining. The Results section on clinical relevance reports more vascular invasion and satellite lesions in S1 tumors and a significantly greater risk of early recurrence after surgical resection. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While the CTNNB1-class was correlated with CTNNB1-mutations, nuclear β-catenin staining and tumor diameter >3cm (6), Wnt-TGFβ-class was associated with TGF-β activation, cytoplasmic β-catenin staining, vascular invasion, satellitosis and greater risk of early recurrence after surgical resection (8).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Supportedcites [6] Chiang, 2008, Focal gains of VEGFA and molecular classification of hepatocellular carcinoma, Cancer Res source
The Results section, “Gene expression classes are associated with signaling pathway alterations,” reports that the CTNNB1-associated class was significantly enriched for CTNNB1 exon 3 mutations and nuclear localization, and was associated with tumor diameters greater than 3 cm. This supports all three associations attributed to the source. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Although several studies have implicated these Wnt-related miRNAs in Wnt-signaling, including the association of miR-375 expression to CTNNB1-mutation (32), no Wnt-class-specific miRNA expression profiles or Wnt-related miRNA-signatures have been described so far.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Supportedcites [32] Ladeiro, 2008, MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations, Hepatology source
The citation is attached to the association of miR-375 expression with CTNNB1 (β-catenin) mutation, not to the subsequent statement that no Wnt-class-specific signature had been described. The Results section on genetic features in HCC reports markedly reduced miR-375 expression in tumors with an activating β-catenin mutation; the HCA results report the same association. No page number is available in our copy. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“While some studies reported pathway activation without detection of nuclear β-catenin, others described negative feedback loops that activate pathway repressors or suppress pathway activators in Wnt-signaling (33).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Partly supportedcites [33] Khan, 2007, Analysis of endogenous LRP6 function reveals a novel feedback mechanism by which Wnt negatively regulates its receptor, Mol Cell Biol sourceExperimental — accuracy not yet measured
The Discussion (page not provided) identifies a Wnt-driven negative feedback mechanism that reduces expression of LRP6, a pathway-activating receptor. The paper does not report pathway activation without detection of nuclear β-catenin; it describes β-catenin translocation to the nucleus during canonical signaling. It also does not show activation of a pathway repressor. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The only FDA-approved drug for advanced HCC, sorafenib is well tolerated in cirrhotic patients (2) and inhibits several tyrosine kinases (e.g. VEGF, PDGFR, ERK/AKT, Ras, etc.), and their downstream oncogenic pathways (35).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Partly supportedcites [2] Llovet, 2008, Sorafenib in advanced hepatocellular carcinoma, N Engl J Med sourceExperimental — accuracy not yet measured
Citation (2) is attached to the tolerability claim, not the mechanism claim cited to (35). The Safety section reports that adverse events were predominantly mild or moderate, but the Patients and Results sections show that the trial enrolled almost entirely people with Child-Pugh class A liver function. It does not establish tolerability across cirrhotic patients with more impaired liver function. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [35] Iyer, 2010, Sorafenib: a clinical and pharmacologic review, Expert Opin Pharmacother source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“accompanied by decreased tumor volume and increased survival of treated animals.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CTNNB1-class was characterized by up-regulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Abstract > Results
plaincorrelationaln = 138- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while Wnt-TGFβ-class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Abstract > Results
plaincorrelationaln = 177- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and was further classified as CTNNB1-class [138 cases (21.5%)] or Wnt-TGFβ-class [177 cases (27.6%)]”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Abstract > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“showed significant dysregulation of 36 and 48 Wnt-pathway-mRNAs, respectively (FDR<0.05)”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tumors of the CTNNB1- (24/91, 26.4%) and Wnt-TGFβ-classes (23/91, 25.3%).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CTNNB1-class was characterized by CDH1 down-regulation, and a significant number of potentially inhibiting alterations (Suppl. Fig 1).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While 19 Wnt-related-miRNAs were significantly dysregulated in CTNNB1-, only 4 miRNAs were differentially expressed in the Wnt-TGFβ-class.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our validation set 76/144 (52.8%) samples had active Wnt-signaling, with 35 (24.3%) belonging to the CTNNB1- and 41 (28.5%) to the Wnt-TGFβ-class.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Their corresponding gene-signatures of dysregulated Wnt-pathway-mRNAs were associated with the CTNNB1- and Wnt-TGFβ-classes (p<0.001 and p=0.005, respectively) (Fig. 3).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, CTNNB1- and Wnt-TGFβ-class express liver-related and classical Wnt-target-genes, respectively, which are significantly correlated to the expression of class-specific transcription factors.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“β-catenin staining distribution was similar in the training and validation cohorts (Suppl. Table 9).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall the prediction accuracy of our signature was of 91% (Specificity =87%, Sensitivity = 100%; Suppl. Fig. 4).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
plainn = 407- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After sorafenib treatment, GLUL and LGR5 were significantly down-regulated in HCC murine xenografts, and TBX3 showed a trend of decreased expression (Fig. 5B).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Sorafenib alters Wnt-signaling in vitro and in vivo
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: HepG2 cells express a truncated β-catenin lacking the Ser/Thr domain that regulates its degradation, and SNU398 cells have a point mutation in a key Ser in the same domain (S37C).
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, the expression of Wnt-related transcription factors appears to be highly class-specific and significantly correlates to liver-related (CTNNB1-class) or classical (Wnt-TGFβ-class) Wnt-target-genes.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
hedgedcorrelationaln = 642- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Abstract > Conclusions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The HCC samples analyzed are representative of all HCC patients, so that the two Wnt-related classes account for half of all HCC patients.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“CTNNB1- and Wnt-TGFβ-class marker genes were excluded from the WntGenes-signatures before the validation analyses.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Materials and Methods > Genomic profiling of Wnt-related mRNAs and miRNAs
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although both Wnt-related molecular classes show clear alteration of the Wnt-pathway at the mRNA and miRNA level, only the CTNNB1-class displayed increased cytoplasmic and nuclear β-catenin and glutamine synthetase by immunostaining.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Written consents from patients, and institutional review board approvals were obtained from all institutions.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Materials and Methods > Human samples, mRNA and miRNA expression arrays data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal studies were done upon Mount Sinai School of Medicine Institutional Animal Care and Use Committee (IACUC) approval.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Materials and Methods > Animal Experiments
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data suggest that sorafenib can decrease Wnt/β-catenin signaling by modulating transcriptional activity through the TCF/LEF site and reduces β-catenin protein levels in liver cancer cells.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Sorafenib alters Wnt-signaling in vitro and in vivo
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: HepG2 cells express a truncated β-catenin lacking the Ser/Thr domain that regulates its degradation, and SNU398 cells have a point mutation in a key Ser in the same domain (S37C).
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, we demonstrate that sorafenib can modulate β-catenin/Wnt-signaling in liver cancer cells, and in CTNNB1-class-like HepG2 xenograft tumors in mice.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: HepG2 cells express a truncated β-catenin lacking the Ser/Thr domain that regulates its degradation, and SNU398 cells have a point mutation in a key Ser in the same domain (S37C).
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Several Wnt-pathway proteins show class-specific dysregulation at the membrane, cytoplasm and nucleus, reinforcing the presence of two different, active Wnt-pathways in liver cancer.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Since a TP53-mutation signature reportedly predicts mutation in breast cancer accurately (15), we aimed to estimate CTNNB1-mutations with a mutation-signature generated in our training set.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [15] Coutant, 2011, Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers, Clin Cancer Res source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At the protein level we confirmed Wnt-pathway activation in CTNNB1-class by positive nuclear and cytoplasmic β-catenin immunostaining, while in Wnt-TGFβ-class β-catenin staining remained membranous.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Its prediction accuracy was 91% when tested in an independent dataset (5) and it was enriched in CTNNB1-class in 6 independent HCC datasets, underscoring the idea that CTNNB1-Wnt is activated and driven by CTNNB1- mutations in HCC.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Regarding TCF4 over-expression, it was previously related to classical Wnt-target-genes expression (e.g. CCNDs or MMPs), even though isoform specific functions remain unclear and would require further analysis (30).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [30] Zhao, 2004, Aberrant expression and function of TCF4 in the proliferation of hepatocellular carcinoma cell line BEL-7402, Cell Res source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“However, all efforts to develop and translate effective and safe Wnt-pathway modulators into the clinical setting have been complicated by the multifaceted nature of Wnt-signaling (4, 15).”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [4] Klaus, 2008, Wnt signalling and its impact on development and cancer, Nat Rev Cancer source
- Not checked — no full text of the sourcecites [15] Coutant, 2011, Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers, Clin Cancer Res source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Glutamine synthetase staining as a surrogate of active β-catenin-signaling was only enriched in the CTNNB1-class, validating the existence of liver-related Wnt-target-genes at the protein level.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The fact that half of the HCC samples displayed activation of Wnt-signaling points to the importance of this signaling cascade in hepatocarcinogenesis and reinforces the need for drugs targeting this pathway.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The publicly available HCC genomic datasets and the HCC samples analyzed in this study are representative of HCC patients generally.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The current data reveal a potential off-target effect of sorafenib, and demonstrate its ability to reduce β-catenin/Wnt-signaling in several experimental models of liver cancer.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: HepG2 cells express a truncated β-catenin lacking the Ser/Thr domain that regulates its degradation, and SNU398 cells have a point mutation in a key Ser in the same domain (S37C).
The paper relies on this without support.
The HCC samples analyzed are representative of all HCC patients, so that the two Wnt-related classes account for half of all HCC patients.
“accounting for half of all HCC patients.”
The paper relies on this without support.
There is no universally accepted molecular classification for HCC.
“However, there is no universally accepted molecular classification for this disease.”
The paper relies on this without support.
HepG2 cells express a truncated β-catenin lacking the Ser/Thr domain that regulates its degradation, and SNU398 cells have a point mutation in a key Ser in the same domain (S37C).
“HepG2 express a truncated β-catenin lacking the Ser/Thr domain that regulates its degradation whereas SNU398 have a point mutation in a key Ser in the same domain (S37C).”
The paper relies on this without support.
The publicly available HCC genomic datasets and the HCC samples analyzed in this study are representative of HCC patients generally.
“In an additional approach we interrogated 5 publicly available HCC genomic datasets representing a total of 407 patients to assess the relevance of Wnt-activation in HCC and to further confirm our class-specific Wnt-genes expression profiles.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > Abstract > Experimental Design
“immunohistochemistry (108 HCCs)”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
“Strong nuclear and cytoplasmic β-catenin staining was observed in 28/35 (80%) CTNNB1-class samples compared to 18/108 (16.6%) of non-Wnt HCC samples (p<0.001)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
“In our validation set 76/144 (52.8%) samples had active Wnt-signaling, with 35 (24.3%) belonging to the CTNNB1- and 41 (28.5%) to the Wnt-TGFβ-class.”
§ Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib > RESULTS > Molecular portrait of two human Wnt HCC subclasses: CTNNB1 and Wnt-TGFβ
“18/108 (16.6%) of non-Wnt HCC samples”
Citations
Cites
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Self-citationSorafenib in Advanced Hepatocellular Carcinoma
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Cited by
Sorted by citations
Llovet, J. M., Kelley, R. K., Villanueva, A., Singal, A. G., Pikarsky, E., Roayaie, S., Lencioni, R., Koike, K., Zucman-Rossi, J., & Finn, R. S. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-00240-3 · Cited by 7,055
Self-citationLlovet, J. M., Zucman-Rossi, J., Pikarsky, E., Sangro, B., Schwartz, M., Sherman, M., & Gores, G. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.18 · Cited by 2,531
Self-citationMolecular therapies and precision medicine for hepatocellular carcinoma
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Self-citationGenetic landscape and biomarkers of hepatocellular carcinoma
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Self-citationIntegrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma
Gao, Q., Zhu, H., Dong, L., Shi, W., Chen, R., Song, Z., Huang, C., Li, J., Dong, X., Zhou, Y., et al. (2019) · Cell · doi:10.1016/j.cell.2019.08.052 · Cited by 1,096
Metadata
- Authors
- Lachenmayer, A., Alsinet, C., Savic, R., Cabellos, L., Toffanin, S., Hoshida, Y., Villanueva, A., Minguez, B., Newell, P., Tsai, H.-W., Barretina, J., Thung, S., Ward, S. C., Bruix, J., Mazzaferro, V., Schwartz, M., Friedman, S. L., & Llovet, J. M.
- Affiliations
- Düsseldorf University Hospital (DE)
- Authors' Affiliations: 1Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine; Tisch Cancer Institute; Division of Surgical Oncology, Department of Surgery; Transplant Institute; Department of Pathology), Mount Sinai School of Medicine, New York, New York; 2Department of General-, Visceral- and Pediatric Surgery, University Hospital Düsseldorf, Düsseldorf, Germany; 3Barcelona Clinic Liver Cancer Group (BCLC; HCC Translational Research Laboratory and Liver Unit), Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona; 4Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; 5Hepato-Oncology Group, Department of Surgery and Experimental Oncology, National Cancer Institute, Milan, Italy; 6Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and 7Hepatobiliary Surgery Section, Providence Portland Medical Center, Portland, Oregon
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-09-15
- Volume
- 18
- Issue
- 18
- Pages
- 4997-5007
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3446854
- OpenAlex
- W2148305615
- Cited by
- 306
- References
- 41
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 15 · 2023: 24 · 2022: 28 · 2021: 27 · 2020: 19 · 2019: 19 · 2018: 21 · 2017: 31 · 2016: 33 · 2015: 23 · 2014: 17 · 2013: 15 · 2012: 2
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Clinical Cancer Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (1R01 DK 076986-01, R01DK076986, 1R01DK56621, 1R01DK37340, R01 DK056621, R01 DK037340)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- Wnt signaling, sorafenib, CTNNB1 mutation, β-catenin, molecular classification, liver cancer cell lines, tumor xenografts, glutamine synthetase, Lgr5, TBX3, Wnt target genes
- MeSH terms
- Sorafenib, Animals, Antineoplastic Agents, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Niacinamide, Phenylurea Compounds, Biomarkers, Tumor, Reproducibility of Results, Cluster Analysis, Transforming Growth Factor beta, Gene Expression Profiling, Genomics, Cell Line, Tumor, Protein Kinase Inhibitors, Wnt Proteins, beta Catenin, Mice, Hep G2 Cells, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-23, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-23 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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