Oncofetal Gene SALL4 in Aggressive Hepatocellular Carcinoma
Open accessAbstract
BACKGROUND: Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment. METHODS: We screened specimens obtained from patients with primary hepatocellular carcinoma for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we used in vitro functional and in vivo xenograft assays. RESULTS: SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have hepatocellular carcinoma and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (the phosphatase and tensin homologue protein) and inhibited tumor formation in xenograft models in vivo. CONCLUSIONS: SALL4 is a marker for a progenitor subclass of hepatocellular carcinoma with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma. (Funded by the Singapore National Medical Research Council and others.).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The reappearance of SALL4 is associated with drug resistance in leukemia, lung, and breast cancer, and the onset of progenitor type hepatocellular carcinoma.
“The reappearance of SALL4 is associated with drug resistance in leukemia, lung, and breast cancer, and the onset of progenitor type hepatocellular carcinoma (Yong et al, 2013).”
From Targeting transcription factors through an IMiD independent zinc finger domain (2025) · cites this paper as Yong et al, 2013
The Abstract Results and Discussion report that SALL4 is reexpressed in a subgroup of hepatocellular carcinomas with progenitor-like features. They do not establish that reexpression marks the onset of that subtype, and the passages found do not link SALL4 to drug resistance in leukemia, lung cancer, or breast cancer. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPharmacological peptides that specifically disrupt the interaction between SALL4 and HDAC1 have been tested with success as therapeutic agents in acute myeloid leukemia and hepatocarcinoma.
“Pharmacological peptides that specifically disrupt the interaction between SALL4 and HDAC1 have been tested with success as therapeutic agents both in acute myeloid leukemia and hepatocarcinoma [65, 68].”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [68]
In Results (‘Targeting SALL4 by a Novel Peptide’; page unavailable), a SALL4 peptide reduced hepatocellular carcinoma cell viability and tumor loads in a mouse xenograft model. The paper says the peptide blocks SALL4’s interaction with the HDAC-containing NuRD complex, not specifically with HDAC1; it describes potential therapy based on preclinical tests, not a successful treatment in patients. This paper does not report peptide testing in acute myeloid leukemia. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSALL4 is overexpressed in many cancers with poor prognosis.
“SALL4 is overexpressed in many cancers with poor prognosis 61-67”
From Tetramerisation governs SALL transcription factor function in development and disease (2025) · cites this paper as [64]
The Results section reports that SALL4 is reexpressed in a subgroup of hepatocellular carcinomas and that patients with high SALL4 expression have a worse prognosis. The paper does not establish the same prognosis association across many cancer types, so the claim extends beyond its findings. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSALL4 is a zinc finger transcription factor important for many cancers, most notably hepatocellular carcinoma (HCC).
“SALL4 is a zinc finger transcription factor that is important for many cancers, most notably hepatocellular carcinoma (HCC) (Yong et al, 2013), lung cancer (Kobayashi et al, 2011a), ovarian cancer (Yang et al, 2016), breast cancer (Kobayashi et al, 2011b), myelodysplastic syndrome (MDS) (Liu et al, 2022), and acute myeloid leukemia (AML) (Li et al, 2013; Ma et al, 2006).”
From Targeting transcription factors through an IMiD independent zinc finger domain (2025) · cites this paper as Yong et al, 2013
SALL4 has been dubbed an 'oncofetal' gene.
“Due to its re-expression in cancers, SALL4 has been dubbed an ‘oncofetal’ gene27.”
From Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4 (2021) · cites this paper as [27]
Sall4 was recently identified as a "targetable marker" for an aggressive subset of HCC.
“Furthermore, Sall4 was recently identified as a “targetable marker” for an aggressive subset of HCC (Yong et al., 2013).”
From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Yong et al., 2013
Lung cancer cell lines expressing high levels of SALL4 are sensitive to the HDAC1 inhibitor Entinostat.
“Lung cancer cell lines expressing high levels of SALL4 are sensitive to the HDAC1 inhibitor Entinostat suggesting the use of this drug as a potential treatment for lung cancer [68].”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [68]
The Results section, “Targeting SALL4 by a Novel Peptide” (page unavailable), reports reduced viability in SALL4-expressing hepatocellular carcinoma cells treated with a SALL4 peptide; trichostatin A was used as a control. Searches for Entinostat, HDAC1, and SALL4-high lung cancer cell lines found no passage testing the claimed drug sensitivity or proposing Entinostat for lung cancer. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Ferlay, J., Shin, H., Bray, F., Forman, D., Mathers, C. D., & Parkin, D. M. (2010) · International Journal of Cancer · doi:10.1002/ijc.25516 · Cited by 21,271 · see citing works
Ben‐Porath, I., Thomson, M., Carey, V. J., Ge, R., Bell, G. W., Regev, A., & Weinberg, R. A. (2008) · Nature Genetics · doi:10.1038/ng.127 · Cited by 2,523 · see citing works
Yoshida, M., Kijima, M., Akita, M., & Beppu, T. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44885-x · Cited by 1,856 · see citing works
A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells
Lee, J., Heo, J., Libbrecht, L. J., Chu, I., Kaposi-Novák, P., Calvisi, D. F., Mikaelyan, A. S., Roberts, L. R., Demetris, A. J., Sun, Z., et al. (2006) · Nature Medicine · doi:10.1038/nm1377 · Cited by 953 · see citing works
Focal Gains of <i>VEGFA</i> and Molecular Classification of Hepatocellular Carcinoma
Chiang, D. Y., Villanueva, A., Hoshida, Y., Peix, J., Newell, P., Minguez, B., LeBlanc, A. C., Donovan, D. J., Thung, S. N., Solé, M., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0742 · Cited by 719 · see citing works
Keating, G. M., & Santoro, A. (2009) · Drugs · doi:10.2165/00003495-200969020-00006 · Cited by 482 · see citing works
Ma, Y., Cui, W., Yang, J., Qu, J., Di, C., Amin, H. M., Lai, R., Ritz, J., Krause, D. S., & Chai, L. (2006) · Blood · doi:10.1182/blood-2006-02-001594 · Cited by 215 · see citing works
Self-citationSal-like protein 4 (SALL4), a stem cell biomarker in liver cancers
Oikawa, T., Kamiya, A., Zeniya, M., Chikada, H., Hyuck, A. D., Yamazaki, Y., Wauthier, E., Tajiri, H., Miller, L. D., Wang, X. W., et al. (2012) · Hepatology · doi:10.1002/hep.26159 · Cited by 195 · see citing works
Identification of a Cholangiocarcinoma-Like Gene Expression Trait in Hepatocellular Carcinoma
Woo, H. G., Lee, J., Yoon, J., Kim, C. Y., Lee, H., Jang, J. J., Yi, N., Suh, K., Lee, K. U., Park, E. S., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-2823 · Cited by 191 · see citing works
Murine inner cell mass-derived lineages depend on Sall4 function
Elling, U., Klasen, C., Eisenberger, T., Anlag, K., & Treier, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607884103 · Cited by 186 · see citing works
Differential roles of Sall4 isoforms in embryonic stem cell pluripotency
Rao, S., Zhen, S., Roumiantsev, S., McDonald, L. T., Yuan, G.-C., & Orkin, S. H. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00419-10 · Cited by 173 · see citing works
Lu, J., Jeong, H., Kong, N., Yang, Y., Carroll, J., Luo, H. R., Silberstein, L. E., YupoMa, & Chai, L. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005577 · Cited by 168 · see citing works
Self-citationCao, D., Humphrey, P. A., & Allan, R. W. (2009) · Cancer · doi:10.1002/cncr.24308 · Cited by 155 · see citing works
A Novel SALL4/OCT4 Transcriptional Feedback Network for Pluripotency of Embryonic Stem Cells
Yang, J., Gao, C., Chai, L., & Ma, Y. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010766 · Cited by 152 · see citing works
Self-citationRegulation and function of Spalt proteins during animal development
de Celis, J. F., & Barrio, R. (2009) · The International Journal of Developmental Biology · doi:10.1387/ijdb.072408jd · Cited by 137 · see citing works
Diagnostic Utility of SALL4 in Extragonadal Yolk Sac Tumors
Wang, F., Liu, A., Peng, Y. S., Rakheja, D., Wei, L., Xue, D., Allan, R. W., Molberg, K. H., Li, J., & Cao, D. (2009) · The American Journal of Surgical Pathology · doi:10.1097/pas.0b013e3181ad25d5 · Cited by 126 · see citing works
Sall4 regulates cell fate decision in fetal hepatic stem/progenitor cells
Oikawa, T., Kamiya, A., Kakinuma, S., Zeniya, M., Nishinakamura, R., Tajiri, H., & Nakauchi, H. (2009) · Gastroenterology · doi:10.1053/j.gastro.2008.11.018 · Cited by 108 · see citing works
Cui, W., Kong, N. R., Ma, Y., Amin, H. M., Lai, R. L., & Chai, L. (2006) · Modern Pathology · doi:10.1038/modpathol.3800694 · Cited by 83 · see citing works
Self-citationWatanabe (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.929 · Cited by 82 · see citing works
Gao, C., Dimitrov, T., Yong, K. J., Tatetsu, H., Jeong, H.-W., Luo, H. R., Bradner, J. E., Tenen, D. G., & Chai, L. (2013) · Blood · doi:10.1182/blood-2012-04-424275 · Cited by 65 · see citing works
Self-citationMukhopadhyay, N. K., Weisberg, E., Gilchrist, D., Bueno, R., Sugarbaker, D. J., & Jaklitsch, M. T. (2006) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2005.06.059 · Cited by 61 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Human primary liver cancer–derived organoid cultures for disease modeling and drug screening
Broutier, L., Mastrogiovanni, G., Verstegen, M. M., Francies, H. E., Gavarró, L. M., Bradshaw, C. R., Allen, G. E., Arnes-Benito, R., Sidorova, O., Gaspersz, M. P., et al. (2017) · Nature Medicine · doi:10.1038/nm.4438 · Cited by 1,471 · see citing works
“Thus, EpCAM, was highly expressed in all CCs (CC-1-3) and CHCs (CHC-1-2) tumouroids and corresponding patients’ tissues, but absent on HCCs tumouroids and tissues (Fig.”
InfluentialYuan, J.-H., Liu, X.-N., Wang, T.-T., Pan, W., Tao, Q.-F., Zhou, W.-P., Wang, F., & Sun, S.-H. (2017) · Nature Cell Biology · doi:10.1038/ncb3538 · Cited by 367 · see citing works
The nucleosome remodeling and deacetylase complex in development and disease
Basta, J., & Rauchman, M. (2015) · Translational Research · doi:10.1016/j.trsl.2014.05.003 · Cited by 191 · see citing works
SALL4, the missing link between stem cells, development and cancer
Tatetsu, H., Kong, N. R., Chong, G., Amabile, G., Tenen, D. G., & Chai, L. (2016) · Gene · doi:10.1016/j.gene.2016.02.019 · Cited by 130 · see citing works
Self-citationHippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation
Alder, O., Cullum, R., Lee, S., Kan, A. C., Wei, W., Yi, Y., Garside, V. C., Bilenky, M., Griffith, M., Morrissy, A. S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.046 · Cited by 113 · see citing works
“Due to the difficulty of propagating hepatocytes in vitro, HEPG2, a hepatocellular carcinoma (HCC) cell line, is commonly used to represent hepatocytes.”
BackgroundInfluentialSelf-citationZinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression
Kong, N. R., Bassal, M. A., Tan, H. K., Kurland, J. V., Yong, K. J., Young, J. J., Yang, Y., Li, F., Lee, J. D., Liu, Y., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108574 · Cited by 56 · see citing works
Self-citationLiu, T.-C., Vachharajani, N., Chapman, W. C., & Brunt, E. M. (2014) · American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000218 · Cited by 37 · see citing works
SALL4: An Intriguing Therapeutic Target in Cancer Treatment
Moein, S., Tenen, D. G., Amabile, G., & Chai, L. (2022) · Cells · doi:10.3390/cells11162601 · Cited by 35 · see citing works
Self-citationEpigenetic control of melanoma cell invasiveness by the stem cell factor SALL4
Diener, J., Baggiolini, A., Pernebrink, M., Dalcher, D., Lerra, L., Cheng, P. F., Varum, S., Häusel, J., Stierli, S., Treier, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25326-8 · Cited by 34 · see citing works
Signalling pathways and transcriptional regulators orchestrating liver development and cancer
Campbell, S. A., Stephan, T. L., Lotto, J., Cullum, R., Drissler, S., & Hoodless, P. A. (2021) · Development · doi:10.1242/dev.199814 · Cited by 22 · see citing works
SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma
Lospinoso Severini, L., Loricchio, E., Navacci, S., Basili, I., Alfonsi, R., Bernardi, F., Moretti, M., Conenna, M., Cucinotta, A., Coni, S., et al. (2024) · Cell Death & Differentiation · doi:10.1038/s41418-023-01246-6 · Cited by 13 · see citing works
“Pharmacological peptides that speci fi cally disrupt the interaction between SALL4 and HDAC1 have been tested with success as therapeutic agents both in acute myeloid leukemia and hepatocarcinoma [65, 68].”
Targeting transcription factors through an IMiD independent zinc finger domain
Liu, B. H., Liu, M., Radhakrishnan, S., Dai, M.-Y., Jaladanki, C. K., Gao, C., Tang, J. P., Kumari, K., Go, M. L., Vu, K. A. L., et al. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00241-3 · Cited by 8 · see citing works
Self-citationTetramerisation governs SALL transcription factor function in development and disease
Giuliani, S., Chhatbar, K., Wear, M., Guy, J., Mathieson, T., Burdett, H., George, L., Alston, G., Spanos, C., McHugh, T., et al. (2025) · bioRxiv · doi:10.1101/2025.10.27.684836
- Authors
- Yong, K. J., Gao, C., Lim, J. S. J., Yan, B., Yang, H., Dimitrov, T., Kawasaki, A., Ong, C. W., Wong, K.-F., Lee, S., Ravikumar, S., Srivastava, S., Tian, X., Poon, R. T., Fan, S. T., Luk, J. M., Dan, Y. Y., Salto-Tellez, M., Chai, L., & Tenen, D. G.
- Affiliations
- National University of Singapore (SG)
- Brigham and Women's Hospital (US)
- Cancer Science Institute of Singapore (SG)
- Queen Mary Hospital (CN)
- Harvard Stem Cell Institute (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-06-13
- Volume
- 368
- Issue
- 24
- Pages
- 2266-2276
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3781214
- OpenAlex
- W2051298779
- Semantic Scholar
- f8b4576c29429a826d621ab31dc8e9ce16c88360
- Cited by
- 257
- References
- 22
- Citations by year
- 2026: 3 · 2025: 16 · 2024: 11 · 2023: 15 · 2022: 14 · 2021: 22 · 2020: 18 · 2019: 11 · 2018: 21 · 2017: 27 · 2016: 37 · 2015: 25 · 2014: 27 · 2013: 9
- FWCI
- 20.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- New England Journal of Medicine (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion, other-oa)
- Funders
- National Research Foundation
- National Research Foundation Singapore
- National Institutes of Health
- Medical Research Council
- National Medical Research Council
- National Heart, Lung, and Blood Institute (R01HL056745, R01HL092437, R01HL112719, P01HL095489)
- National Cancer Institute (R01CA118316, P01CA066996)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK080665)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- SALL4, hepatocellular carcinoma, oncofetal genes, PTEN, tumor suppressor, prognostic factors, therapeutic target, hepatocarcinogenesis, xenograft tumor formation, cell survival
- MeSH terms
- Adult, Animals, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Mice, Inbred Strains, Prognosis, Transcription Factors, Transplantation, Heterologous, Tumor Cells, Cultured, Biomarkers, Tumor, Gene Expression, Gene Expression Regulation, Neoplastic, PTEN Phosphohydrolase, Mice, Metabolic Networks and Pathways
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.
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 ›
Are you an author, or do you see a problem with this page? Request a review
