CoChat
Sign Up
Cited by 87Cholangiocarcinoma and Gallbladder Cancer StudiesPediatric Hepatobiliary Diseases and TreatmentsBone Tumor Diagnosis and Treatments

Loss of Fbxw7 synergizes with activated Akt signaling to promote c-Myc dependent cholangiocarcinogenesis

Open access
Wang, Jingxiao, Wang, Haichuan, Peters, Michele, Ding, Ning, Ribback, Silvia, Utpatel, Kirsten, Cigliano, Antonio, Dombrowski, Frank +10 more·2019·Journal of Hepatology
DOI 10.1016/j.jhep.2019.05.027PMC PMC6773530
Open this paper in CoChat — free account

Abstract

Background & aims The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized as a tumor suppressor in many cancer types due to its ability to promote the degradation of numerous oncogenic target proteins. Herein, we aimed to elucidate its role in intrahepatic cholangiocarcinoma (iCCA). Methods Herein, we first confirmed that FBXW7 gene expression was reduced in human iCCA specimens. To identify the molecular mechanisms by which FBXW7 dysfunction promotes cholangiocarcinogenesis, we generated a mouse model by hydrodynamic tail vein injection of Fbxw7ΔF, a dominant negative form of Fbxw7, either alone or in association with an activated/myristylated form of AKT (myr-AKT). We then confirmed the role of c-MYC in human iCCA cell lines and its relationship to FBXW7 expression in human iCCA specimens. Results FBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. While forced overexpression of Fbxw7ΔF alone did not induce any appreciable abnormality in the mouse liver, co-expression with AKT triggered cholangiocarcinogenesis and mice had to be euthanized by 15 weeks post-injection. At the molecular level, a strong induction of Fbxw7 canonical targets, including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-MYC was consistently confirmed as a FBXW7 target in human CCA cell lines. Most importantly, selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 only delayed tumorigenesis in the same model. In human iCCA specimens, an inverse correlation between the expression levels of FBXW7 and c-MYC transcriptional activity was observed. Conclusions Downregulation of FBXW7 is ubiquitous in human iCCA and cooperates with AKT to induce cholangiocarcinogenesis in mice via c-Myc-dependent mechanisms. Targeting c-MYC might represent an innovative therapy against iCCA exhibiting low FBXW7 expression. Lay summary There is mounting evidence that FBXW7 functions as a tumor suppressor in many cancer types, including intrahepatic cholangiocarcinoma, through its ability to promote the degradation of numerous oncoproteins. Herein, we have shown that the low expression of FBXW7 is ubiquitous in human cholangiocarcinoma specimens. This low expression is correlated with increased c-MYC activity, leading to tumorigenesis. Our findings suggest that targeting c-MYC might be an effective treatment for intrahepatic cholangiocarcinoma.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.jhep.2019.05.027

Cites

1 of 1 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

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

Flagged first, then by citations

Research works printed but not linked: 48

  1. [1]Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68: 7– 30. 29313949
  2. [2]Sia D, Villanueva A, Friedman SL, Llovet JM. Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis. Gastroenterology 2017; 152: 745– 761. 28043904 PMC12160040
  3. [3]Lee SY, Cherqui D. Operative management of cholangiocarcinoma. Semin Liver Dis 2013; 33: 248– 261. 23943105
  4. [4]Khan SA, Emadossadaty S, Ladep NG, Thomas HC, Elliott P, Taylor-Robinson SD, Rising trends in cholangiocarcinoma: is the ICD classification system misleading us? J Hepatol 2012; 56: 848– 854. 22173164
  5. [5]Yamamoto M, Takasaki K, Otsubo T, Katsuragawa H, Katagiri S. Recurrence after surgical resection of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2001; 8: 154– 157. 11455472
  6. [6]Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013; 145: 1215– 1229. 24140396 PMC3862291
  7. [7]Hyder O, Hatzaras I, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Recurrence after operative management of intrahepatic cholangiocarcinoma. Surgery 2013; 153: 811– 818. 23499016 PMC3980567
  8. [8]Mertens JC, Rizvi S, Gores GJ. Targeting cholangiocarcinoma. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2018; 1864: 1454– 1460. 28844952 PMC6013079
  9. [9]Cao J, Ge MH, Ling ZQ. Fbxw7 Tumor Suppressor: A Vital Regulator Contributes to Human Tumorigenesis. Medicine (Baltimore) 2016; 95: e2496. 26886596 PMC4998596
  10. [10]Yeh CH, Bellon M, Nicot C. FBXW7: a critical tumor suppressor of human cancers. Mol Cancer 2018; 17: 115. 30086763 PMC6081812
  11. [11]Li M, Ouyang L, Zheng Z, Xiang D, Ti A, Li L, E3 ubiquitin ligase FBW7alpha inhibits cholangiocarcinoma cell proliferation by downregulating c-Myc and cyclin E. Oncol Rep 2017; 37: 1627– 1636. 28184929
  12. [12]Kanatsu-Shinohara M, Onoyama I, Nakayama KI, Shinohara T. Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal. Proceedings of the National Academy of Sciences of the United States of America 2014; 111: 8826– 8831. 24879440 PMC4066470
  13. [13]Tu K, Yang W, Li C, Zheng X, Lu Z, Guo C, Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma. Mol Cancer 2014; 13: 110. 24884509 PMC4035898
  14. [14]Malyukova A, Dohda T, von der Lehr N, Akhoondi S, Corcoran M, Heyman M, The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res 2007; 67: 5611– 5616. 17575125
  15. [15]Aydin IT, Melamed RD, Adams SJ, Castillo-Martin M, Demir A, Bryk D, FBXW7 mutations in melanoma and a new therapeutic paradigm. J Natl Cancer Inst 2014; 106: dju107. 24838835 PMC4081626
  16. [16]Mao JH, Kim IJ, Wu D, Climent J, Kang HC, DelRosario R, FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science 2008; 321: 1499– 1502. 18787170 PMC2849753
  17. [17]Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res 2007; 67: 9006– 9012. 17909001
  18. [18]Yang H, Lu X, Liu Z, Chen L, Xu Y, Wang Y, FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells. Oncotarget 2015; 6: 6310– 6325. 25749036 PMC4467439
  19. [19]Enkhbold C, Utsunomiya T, Morine Y, Imura S, Ikemoto T, Arakawa Y, Loss of FBXW7 expression is associated with poor prognosis in intrahepatic cholangiocarcinoma. Hepatol Res 2014; 44: E346– 352. 24552289
  20. [20]Imura S, Tovuu LO, Utsunomiya T, Morine Y, Ikemoto T, Arakawa Y, Role of Fbxw7 expression in hepatocellular carcinoma and adjacent non-tumor liver tissue. J Gastroenterol Hepatol 2014; 29: 1822– 1829. 24731221
  21. [21]Chang MT, Asthana S, Gao SP, Lee BH, Chapman JS, Kandoth C, Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nature biotechnology 2016; 34: 155– 163. PMC4744099 26619011
  22. [22]Chang MT, Bhattarai TS, Schram AM, Bielski CM, Donoghue MTA, Jonsson P, Accelerating Discovery of Functional Mutant Alleles in Cancer. Cancer discovery 2018; 8: 174– 183. 29247016 PMC5809279
  23. [23]Gu Z, Mitsui H, Inomata K, Honda M, Endo C, Sakurada A, The methylation status of FBXW7 beta-form correlates with histological subtype in human thymoma. Biochemical and biophysical research communications 2008; 377: 685– 688. 18938137
  24. [24]Cassia R, Moreno-Bueno G, Rodriguez-Perales S, Hardisson D, Cigudosa JC, Palacios J. Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. The Journal of pathology 2003; 201: 589– 595. 14648662
  25. [25]Ishii N, Araki K, Yokobori T, Watanabe A, Tsukagoshi M, Kubo N, Poor prognosis in cholangiocarcinoma patients with low FBXW7 expression is improved by chemotherapy. Oncol Lett 2017; 13: 3653– 3661. 28521468 PMC5431321
  26. [26]Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science signaling 2013; 6:pl 1. PMC4160307 23550210
  27. [27]Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer discovery 2012; 2: 401– 404. 22588877 PMC3956037
  28. [28]Schmitz KJ, Lang H, Wohlschlaeger J, Sotiropoulos GC, Reis H, Schmid KW, AKT and ERK½ signaling in intrahepatic cholangiocarcinoma. World J Gastroenterol 2007; 13: 6470– 6477. 18161916 PMC4611285
  29. [29]Calvisi DF, Wang C, Ho C, Ladu S, Lee SA, Mattu S, Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology 2011; 140: 1071– 1083. 21147110 PMC3057329
  30. [30]Wu JC, Merlino G, Fausto N. Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha. Proceedings of the National Academy of Sciences of the United States of America 1994; 91: 674– 678. 7904757 PMC43011
  31. [31]Pei T, Li Y, Wang J, Wang H, Liang Y, Shi H, YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 2015; 6: 17206– 17220. 26015398 PMC4627302
  32. [32]Zhang Q, Zhang Y, Parsels JD, Lohse I, Lawrence TS, Pasca di Magliano M, Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation. Neoplasia 2016; 18: 666– 673. 27764699 PMC5071541
  33. [34]Wang J, Dong M, Xu Z, Song X, Zhang S, Qiao Y, Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene 2018; 37: 3229– 3242. 29545603 PMC6002343
  34. [35]Xin B, Yamamoto M, Fujii K, Ooshio T, Chen X, Okada Y, Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways. Oncogene 2017; 36: 5087– 5097. 28481866 PMC5596209
  35. [36]Zhu J, Blenis J, Yuan J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proceedings of the National Academy of Sciences of the United States of America 2008; 105: 6584– 6589. 18451027 PMC2373325
  36. [37]Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J 2004; 23: 2116– 2125. 15103331 PMC424394
  37. [38]King B, Trimarchi T, Reavie L, Xu L, Mullenders J, Ntziachristos P, The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell 2013; 153: 1552– 1566. 23791182 PMC4146439
  38. [39]Ishikawa Y, Hosogane M, Okuyama R, Aoyama S, Onoyama I, Nakayama KI, Opposing functions of Fbxw7 in keratinocyte growth, differentiation and skin tumorigenesis mediated through negative regulation of c-Myc and Notch. Oncogene 2013; 32: 1921– 1932. 22665065
  39. [40]Xi Z, Yao M, Li Y, Xie C, Holst J, Liu T, Guttiferone K impedes cell cycle re-entry of quiescent prostate cancer cells via stabilization of FBXW7 and subsequent c-MYC degradation. Cell Death Dis 2016; 7: e2252. 27253416 PMC5143372
  40. [41]Tu K, Zheng X, Zhou Z, Li C, Zhang J, Gao J, Recombinant human adenovirus-p53 injection induced apoptosis in hepatocellular carcinoma cell lines mediated by p53-Fbxw7 pathway, which controls c-Myc and cyclin E. PLoS One 2013; 8: e68574. 23840897 PMC3698167
  41. [42]Yeh CH, Bellon M, Nicot C. FBXW7: a critical tumor suppressor of human cancers. Molecular Cancer 2018; 17: 115. 30086763 PMC6081812
  42. [43]Goeppert B, Ernst C, Baer C, Roessler S, Renner M, Mehrabi A, Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma. Epigenetics 2016; 11: 780– 790. 27593557 PMC5221660
  43. [44]Liu Y, Ren S, Castellanos-Martin A, Perez-Losada J, Kwon YW, Huang Y, Multiple novel alternative splicing forms of FBXW7α have a translational modulatory function and show specific alteration in human cancer. Plos One 2012; 7: e49453. 23166673 PMC3498124
  44. [45]Jung M, Gelato KA, Fernández-Montalván A, Siegel S, Haendler B. Targeting BET bromodomains for cancer treatment. Epigenomics 2015; 7: 487– 501. 26077433
  45. [46]Li X, Zhang XA, Xie W, Li X, Huang S. MYC-mediated synthetic lethality for treatment of hematological malignancies. Current Cancer Drug Targets 2015; 15 −. 25564254
  46. [47]Lee JW, Soung YH, Kim HJ, Park WS, Nam SW, Kim SH, Mutational analysis of the hCDC4 gene in gastric carcinomas. European Journal of Cancer 2006; 42: 2369– 2373. 16824748
  47. [48]Spruck CH, Heimo S, Olle S, Müller HM, Michael H, Elisabeth MH, hCDC4 gene mutations in endometrial cancer. Cancer Research 2002; 62: 4535. 12183400
  48. [49]Zhaodi G, Kenichi I, Hidetoshi M, Akira H. Promoter hypermethylation is not the major mechanism for inactivation of the FBXW7 beta-form in human gliomas. Genes & Genetic Systems 2008; 83: 347– 352. 18931460

Cited by

Sorted by citations

Authors
Wang, J., Wang, H., Peters, M., Ding, N., Ribback, S., Utpatel, K., Cigliano, A., Dombrowski, F., Xu, M., Chen, X., Song, X., Che, L., Evert, M., Cossu, A., Gordan, J., Zeng, Y., Chen, X., & Calvisi, D. F.
Affiliations
  • Beijing University of Chinese Medicine (CN)
  • University of California, San Francisco (US)
  • Universität Greifswald (DE)
  • Capital Medical University (CN)
  • University of Regensburg (DE)
  • Azienda Ospedaliero Universitaria di Sassari (IT)
  • Sichuan University (CN)
  • Universitätsmedizin Greifswald (DE)
Corresponding author
  • Zeng, Yong
  • Chen, Xin
  • Calvisi, Diego F.
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2019-10
Volume
71
Issue
4
Pages
742-752
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2019.05.027
PMC
PMC6773530
OpenAlex
W2949088233
Cited by
87
References
1
Citations by year
2026: 2 · 2025: 10 · 2024: 8 · 2023: 10 · 2022: 36 · 2021: 11 · 2020: 8 · 2019: 2
FWCI
13.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UnissResearch (Università degli Studi di Sassari) (submittedVersion, cc-by-nc-nd)
  • University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Liver Center, University of California, San Francisco
  • National Natural Science Foundation of China
  • Deutsche Forschungsgemeinschaft
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
Keywords
FBXW7, intrahepatic cholangiocarcinoma, cholangiocarcinogenesis, Akt signaling, c-Myc, tumor suppressor, ubiquitin ligase, YAP, Notch2, hydrodynamic tail vein injection, mouse tumor model
MeSH terms
F-Box-WD Repeat-Containing Protein 7, YAP-Signaling Proteins, Animals, Disease Models, Animal, Humans, Liver Neoplasms, Tumor Cells, Cultured, Signal Transduction, Genes, Tumor Suppressor, Proto-Oncogene Proteins c-myc, Cholangiocarcinoma, Cell Cycle Proteins, Adaptor Proteins, Signal Transducing, Mice, Receptor, Notch2, Molecular Targeted Therapy, Carcinogenesis

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