NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis.
Animals
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Cell Movement
/ genetics
Cohort Studies
DNA Mutational Analysis
Female
Gene Expression Regulation, Neoplastic
Humans
Liver
/ pathology
Liver Neoplasms
/ genetics
Male
Mice
Mutation
Proto-Oncogene Proteins c-akt
/ metabolism
Receptors, Notch
/ metabolism
Repressor Proteins
/ genetics
Signal Transduction
/ genetics
Exome Sequencing
Xenograft Model Antitumor Assays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
11
06
2019
accepted:
28
01
2020
revised:
12
12
2019
pubmed:
15
2
2020
medline:
15
12
2020
entrez:
15
2
2020
Statut:
ppublish
Résumé
NOTCH receptor signaling plays a pivotal role in liver homeostasis and hepatocarcinogenesis. However, the role of NOTCH pathway mutations and the NOTCH target gene HES5 in liver tumorigenesis are poorly understood. Here we performed whole-exome sequencing of 54 human HCC specimens and compared the prevalence of NOTCH pathway component mutations with the TCGA-LIHC cohort (N = 364). In addition, we functionally characterized the NOTCH target HES5 and the patient-derived HES5-R31G mutation in vitro and in an orthotopic mouse model applying different oncogenic backgrounds, to dissect the role of HES5 in different tumor subgroups in vivo. We identified nonsynonymous mutations in 14 immediate NOTCH pathway genes affecting 24.1% and 16.8% of HCC patients in the two independent cohorts, respectively. Among these, the HES5-R31G mutation was predicted in silico to have high biological relevance. Functional analyses in cell culture showed that HES5 reduced cell migration and clonogenicity. Further analyses revealed that the patient-derived HES5-R31G mutant protein was non-functional due to loss of DNA binding and greatly reduced nuclear localization. Furthermore, HES5 exhibited a negative feedback loop by directly inhibiting the NOTCH target HES1 and downregulated the pro-proliferative MYC targets ODC1 and LDHA. Interestingly, HES5 inhibited MYC-dependent hepatocarcinogenesis, whereas it promoted AKT-dependent liver tumor formation and stem cell features in a murine model. Thus, NOTCH pathway component mutations are commonly observed in HCC. Furthermore, the NOTCH target gene HES5 has both pro- and anti-tumorigenic functions in liver cancer proposing a driver gene dependency and it promotes tumorigenesis with its interaction partner AKT.
Identifiants
pubmed: 32055024
doi: 10.1038/s41388-020-1198-3
pii: 10.1038/s41388-020-1198-3
pmc: PMC7142020
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Receptors, Notch
0
Repressor Proteins
0
HES5 protein, human
148591-48-4
AKT1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3128-3144Références
Ding L, Bailey MH, Porta-Pardo E, Thorsson V, Colaprico A, Bertrand D, et al. Perspective on oncogenic processes at the end of the beginning of cancer genomics. Cell. 2018;173:305–20 e310.
pubmed: 29625049
pmcid: 5916814
doi: 10.1016/j.cell.2018.03.033
Dugger SA, Platt A, Goldstein DB. Drug development in the era of precision medicine. Nat Rev Drug Discov. 2018;17:183–96.
pubmed: 29217837
doi: 10.1038/nrd.2017.226
Cancer Genome Atlas Research Network. Electronic address wbe, Cancer Genome Atlas Research Network Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327–41 e1323.
doi: 10.1016/j.cell.2017.05.046
Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.
pubmed: 25822088
pmcid: 4587544
doi: 10.1038/ng.3252
Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46:1267–73.
pubmed: 25362482
doi: 10.1038/ng.3126
Bray SJ. Notch signalling in context. Nat Rev Mol cell Biol. 2016;17:722–35.
pubmed: 27507209
doi: 10.1038/nrm.2016.94
Aster JC, Pear WS, Blacklow SC. The varied roles of Notch in cancer. Annu Rev Pathol. 2017;12:245–75.
pubmed: 27959635
doi: 10.1146/annurev-pathol-052016-100127
Morell CM, Strazzabosco M. Notch signaling and new therapeutic options in liver disease. J Hepatol. 2014;60:885–90.
pubmed: 24308992
doi: 10.1016/j.jhep.2013.11.028
Geisler F, Strazzabosco M. Emerging roles of Notch signaling in liver disease. Hepatology. 2015;61:382–92.
pubmed: 24930574
doi: 10.1002/hep.27268
Sun L, Sun G, Yu Y, Coy DH. Is Notch signaling a specific target in hepatocellular carcinoma? Anticancer Agents Med Chem. 2015;15:809–15.
pubmed: 25642981
doi: 10.2174/1871520615666150202102809
Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y, Toffanin S, et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 2012;143:1660–9 e1667.
pubmed: 22974708
doi: 10.1053/j.gastro.2012.09.002
Viatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin C, et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med. 2011;208:1963–76.
pubmed: 21875955
pmcid: 3182062
doi: 10.1084/jem.20110198
Gramantieri L, Giovannini C, Lanzi A, Chieco P, Ravaioli M, Venturi A, et al. Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. Liver Int. 2007;27:997–1007.
pubmed: 17696940
doi: 10.1111/j.1478-3231.2007.01544.x
Zhou L, Zhang N, Song W, You N, Li Q, Sun W, et al. The significance of Notch1 compared with Notch3 in high metastasis and poor overall survival in hepatocellular carcinoma. PLoS ONE. 2013;8:e57382.
pubmed: 23468978
pmcid: 3585338
doi: 10.1371/journal.pone.0057382
Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, Felix K, et al. Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology. 2013;144:1530–42 e1512.
pubmed: 23419361
doi: 10.1053/j.gastro.2013.02.009
Dill MT, Tornillo L, Fritzius T, Terracciano L, Semela D, Bettler B, et al. Constitutive Notch2 signaling induces hepatic tumors in mice. Hepatology. 2013;57:1607–19.
pubmed: 23175466
doi: 10.1002/hep.26165
Evert M, Dombrowski F, Fan B, Ribback S, Chen X, Calvisi DF. On the role of notch1 and adult hepatocytes in murine intrahepatic cholangiocarcinoma development. Hepatology. 2013;58:1857–9.
pubmed: 23526421
doi: 10.1002/hep.26411
Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S, et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest. 2012;122:2911–5.
pubmed: 22797301
pmcid: 3408746
doi: 10.1172/JCI63212
Fu W, Lei C, Yu Y, Liu S, Li T, Lin F, et al. EGFR/Notch antagonists enhance the response to inhibitors of the PI3K-Akt pathway by decreasing tumor-initiating cell frequency. Clin Cancer Res. 2019;25:2835–47.
pubmed: 30670492
doi: 10.1158/1078-0432.CCR-18-2732
Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012;44:760–4.
pubmed: 22634756
doi: 10.1038/ng.2291
Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44:694–8.
pubmed: 22561517
pmcid: 3819251
doi: 10.1038/ng.2256
Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet. 2012;44:1117–21.
pubmed: 22922871
doi: 10.1038/ng.2391
Roessler S, Long EL, Budhu A, Chen Y, Zhao X, Ji J, et al. Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival. Gastroenterology. 2012;142:957–66 e912.
pubmed: 22202459
doi: 10.1053/j.gastro.2011.12.039
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010;24:2463–79.
pubmed: 21078816
pmcid: 2975923
doi: 10.1101/gad.1971610
Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA. 2010;107:2037–42.
pubmed: 20133848
doi: 10.1073/pnas.0914433107
pmcid: 2836706
Nilsson JA, Keller UB, Baudino TA, Yang C, Norton S, Old JA, et al. Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation. Cancer Cell. 2005;7:433–44.
pubmed: 15894264
doi: 10.1016/j.ccr.2005.03.036
Bello-Fernandez C, Packham G, Cleveland JL. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc Natl Acad Sci USA. 1993;90:7804–8.
pubmed: 8356088
doi: 10.1073/pnas.90.16.7804
pmcid: 47231
Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA. 1997;94:6658–63.
pubmed: 9192621
doi: 10.1073/pnas.94.13.6658
pmcid: 21214
Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, et al. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol. 2004;24:5923–36.
pubmed: 15199147
pmcid: 480875
doi: 10.1128/MCB.24.13.5923-5936.2004
Kageyama R, Ohtsuka T, Kobayashi T. The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development. 2007;134:1243–51.
pubmed: 17329370
doi: 10.1242/dev.000786
Chen X, Calvisi DF. Hydrodynamic transfection for generation of novel mouse models for liver cancer research. Am J Pathol. 2014;184:912–23.
pubmed: 24480331
pmcid: 3969989
doi: 10.1016/j.ajpath.2013.12.002
Calvisi DF, Wang C, Ho C, Ladu S, Lee SA, Mattu S, et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140:1071–83.
pubmed: 21147110
doi: 10.1053/j.gastro.2010.12.006
Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12:436.
pubmed: 26099984
doi: 10.1038/nrclinonc.2015.121
Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6.
pubmed: 23632345
pmcid: 3683119
doi: 10.1097/MCG.0b013e3182872f29
Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell. 2016;30:533–47.
pubmed: 27728804
doi: 10.1016/j.ccell.2016.09.003
pmcid: 7789819
Hoare M, Ito Y, Kang TW, Weekes MP, Matheson NJ, Patten DA, et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat Cell Biol. 2016;18:979–92.
pubmed: 27525720
pmcid: 5008465
doi: 10.1038/ncb3397
Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011;479:547–51.
pubmed: 22080947
doi: 10.1038/nature10599
Zender S, Nickeleit I, Wuestefeld T, Sorensen I, Dauch D, Bozko P, et al. A critical role for notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell. 2013;23:784–95.
pubmed: 23727022
doi: 10.1016/j.ccr.2013.04.019
Abitbol S, Dahmani R, Coulouarn C, Ragazzon B, Mlecnik B, Senni N, et al. AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of beta-catenin activation. J Hepatol. 2018;68:1203–13.
pubmed: 29525529
doi: 10.1016/j.jhep.2017.12.018
Liu H, Tang X, Srivastava A, Pecot T, Daniel P, Hemmelgarn B, et al. Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles. Nat Cell Biol. 2015;17:1036–48.
pubmed: 26192440
pmcid: 4526313
doi: 10.1038/ncb3210
Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, Miyachi H, et al. Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science. 2013;342:1203–8.
pubmed: 24179156
doi: 10.1126/science.1242366
Giachino C, Boulay JL, Ivanek R, Alvarado A, Tostado C, Lugert S, et al. A tumor suppressor function for Notch signaling in forebrain tumor subtypes. Cancer Cell. 2015;28:730–42.
pubmed: 26669487
doi: 10.1016/j.ccell.2015.10.008
Kuang SQ, Fang Z, Zweidler-McKay PA, Yang H, Wei Y, Gonzalez-Cervantes EA, et al. Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia. PLoS ONE. 2013;8:e61807.
pubmed: 23637910
pmcid: 3637323
doi: 10.1371/journal.pone.0061807
Chen ZZ, Huang L, Wu YH, Zhai WJ, Zhu PP, Gao YF. LncSox4 promotes the self-renewal of liver tumour-initiating cells through Stat3-mediated Sox4 expression. Nat Commun. 2016;7:12598.
pubmed: 27553854
pmcid: 4999516
doi: 10.1038/ncomms12598
Lachenmayer A, Alsinet C, Savic R, Cabellos L, Toffanin S, Hoshida Y, et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin Cancer Res. 2012;18:4997–5007.
pubmed: 22811581
pmcid: 3446854
doi: 10.1158/1078-0432.CCR-11-2322
Tschaharganeh DF, Xue W, Calvisi DF, Evert M, Michurina TV, Dow LE, et al. p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell. 2014;158:579–92.
pubmed: 25083869
pmcid: 4221237
doi: 10.1016/j.cell.2014.05.051
Liu L, Liu C, Zhang Q, Shen J, Zhang H, Shan J, et al. SIRT1-mediated transcriptional regulation of SOX2 is important for self-renewal of liver cancer stem cells. Hepatology. 2016;64:814–27.
pubmed: 27312708
doi: 10.1002/hep.28690
Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012;44:1111–6.
pubmed: 22941189
pmcid: 3557461
doi: 10.1038/ng.2405
Braccioli L, Vervoort SJ, Puma G, Nijboer CH, Coffer PJ. SOX4 inhibits oligodendrocyte differentiation of embryonic neural stem cells in vitro by inducing Hes5 expression. Stem Cell Res. 2018;33:110–9.
pubmed: 30343100
doi: 10.1016/j.scr.2018.10.005
Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012;18:572–9.
pubmed: 22388089
pmcid: 3364717
doi: 10.1038/nm.2667
Jiang W, Wang XW, Unger T, Forgues M, Kim JW, Hussain SP, et al. Cooperation of tumor-derived HBx mutants and p53-249(ser) mutant in regulating cell proliferation, anchorage-independent growth and aneuploidy in a telomerase-immortalized normal human hepatocyte-derived cell line. Int J Cancer. 2010;127:1011–20.
pubmed: 20017137
pmcid: 2950321
doi: 10.1002/ijc.25118
Ploeger C, Waldburger N, Fraas A, Goeppert B, Pusch S, Breuhahn K, et al. Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma. Hepatology. 2016;64:828–42.
pubmed: 27311882
doi: 10.1002/hep.28684