The almighty MYC: Orchestrating the micro-RNA universe to generate aggressive liver cancer
Authors: Snorri S. Thorgeirsson
Journal: Journal of Hepatology (2011)

Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Cairo S, Wang Y, de Reyniès A, Duroure K, Dahan J, Redon MJ, Fabre M, McClelland M, Wang XW, Croce CM, Buendia MA. PNAS, 2010, November 23, 107(47), 20471–20476. Copyright (2010) by the National Academy of Sciences. Abstract reprinted with permission from the National Academy of Sciences.http://www.ncbi.nlm.nih.gov/pubmed/21059911Abstract: Myc activation has been implicated in the pathogenesis of hepatoblastoma (HB), a rare embryonal neoplasm derived from liver progenitor cells. Here, microRNA (miR) expression profiling of 65 HBs evidenced differential patterns related to developmental stage and Myc activity. Undifferentiated aggressive HBs overexpressed the miR-371–3 cluster with concomitant down-regulation of the miR-100/let-7a-2/miR125b-1 cluster, evoking an ES cell expression profile. ChIP and Myc inhibition assays in hepatoma cells demonstrated that both miR clusters are regulated by Myc in an opposite manner. We show that the two miR clusters exert antagonistic effects on cell proliferation and tumorigenicity. Moreover, their combined deregulation cooperated in modulating the hepatic tumor phenotype, implicating stem cell-like regulation of Myc dependent miRs in poorly differentiated HBs. Importantly, a four-miR signature representative of these clusters efficiently stratified HB patients, and when applied to 241 hepatocellular carcinomas (HCCs), it identified invasive tumors with a poor prognosis. Our data argue that Myc-driven reprograming of miR expression patterns contributes to the aggressive phenotype of liver tumors originating from hepatic progenitor cells. Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Cairo S, Wang Y, de Reyniès A, Duroure K, Dahan J, Redon MJ, Fabre M, McClelland M, Wang XW, Croce CM, Buendia MA. PNAS, 2010, November 23, 107(47), 20471–20476. Copyright (2010) by the National Academy of Sciences. Abstract reprinted with permission from the National Academy of Sciences. http://www.ncbi.nlm.nih.gov/pubmed/21059911 Abstract: Myc activation has been implicated in the pathogenesis of hepatoblastoma (HB), a rare embryonal neoplasm derived from liver progenitor cells. Here, microRNA (miR) expression profiling of 65 HBs evidenced differential patterns related to developmental stage and Myc activity. Undifferentiated aggressive HBs overexpressed the miR-371–3 cluster with concomitant down-regulation of the miR-100/let-7a-2/miR125b-1 cluster, evoking an ES cell expression profile. ChIP and Myc inhibition assays in hepatoma cells demonstrated that both miR clusters are regulated by Myc in an opposite manner. We show that the two miR clusters exert antagonistic effects on cell proliferation and tumorigenicity. Moreover, their combined deregulation cooperated in modulating the hepatic tumor phenotype, implicating stem cell-like regulation of Myc dependent miRs in poorly differentiated HBs. Importantly, a four-miR signature representative of these clusters efficiently stratified HB patients, and when applied to 241 hepatocellular carcinomas (HCCs), it identified invasive tumors with a poor prognosis. Our data argue that Myc-driven reprograming of miR expression patterns contributes to the aggressive phenotype of liver tumors originating from hepatic progenitor cells. One of the most common oncogenic events in human cancer involves the activation of the MYC oncogene. This is not surprising when it is recognized that MYC may regulate as many as 15% of genes in the genome from flies to humans [[1]Eilers M. Eisenman R.N. Myc’s broad reach.Genes Dev. 2008; 22: 2755-2766Crossref PubMed Scopus (722) Google Scholar]. The MYC target genes are involved in diverse biological programs, such as cell cycle, cell growth, protein synthesis, cell adhesion and cytoskeleton, metabolism, apoptosis, angiogenesis, DNA repair, stem cell renewal, and more recently microRNAs (miR). The demonstration that MYC also controls expression of a subset of miRs that include upregulation of six miRs within the miR-17 cluster on chromosome 13 through direct binding to the miR-17 locus [2He L. Thomson J.M. Hemann M.T. Hernando-Monge E. Mu D. Goodson S. et al.A microRNA polycistron as a potential human oncogene.Nature. 2005; 435: 828-833Crossref PubMed Scopus (3094) Google Scholar, 3O’Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. c-Myc-regulated microRNAs modulate E2F1 expression.Nature. 2005; 435: 839-843Crossref PubMed Scopus (2423) Google Scholar] or cause repression of numerous miRs, including miR-23a/b resulting in increased glutamine catabolism [[4]Gao P. Tchernyshyov I. Chang T.C. Lee Y.S. Kita K. Ochi T. et al.c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.Nature. 2009; 458: 762-765Crossref PubMed Scopus (1505) Google Scholar] and let-7 tumor suppressor regulating expression of MYC itself [5Sampson V.B. Rong N.H. Han J. Yang Q. Aris V. Soteropoulos P. et al.MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells.Cancer Res. 2007; 67: 9762-9770Crossref PubMed Scopus (660) Google Scholar, 6Chang T.C. Yu D. Lee Y.S. Wentzel E.A. Arking D.E. West K.M. et al.Widespread microRNA repression by Myc contributes to tumorigenesis.Nat Genet. 2008; 40: 43-50Crossref PubMed Scopus (1082) Google Scholar]. The involvement of MYC in control of numerous miRs further expands the class of critical MYC targets. It is now well recognized that deregulation of miR expression contributes to cancer development via either promotion or inhibition of tumorigenesis [7Medina P.P. Slack F.J. MicroRNAs and cancer: an overview.Cell Cycle. 2008; 7: 2485-2492Crossref PubMed Scopus (289) Google Scholar, 8Iorio M.V. Croce C.M. MicroRNAs in cancer: small molecules with a huge impact.J Clin Oncol. 2009; 27: 5848-5856Crossref PubMed Scopus (830) Google Scholar]. Furthermore, since changes in miR expression correlate with tumor characteristics and clinical course, the therapeutic potential of miRs in cancer is currently being explored [[9]Garzon R. Marcucci G. Croce C.M. Targeting microRNAs in cancer: rationale, strategies and challenges.Nat Rev Drug Discov. 2010; 9: 775-789Crossref PubMed Scopus (1255) Google Scholar]. The convergence of MYC, miRs, and stem cell biology is elegantly illustrated in a recent article by Buendia and her colleagues [[10]Cairo S. Wang Y. de Reyniès A. Duroure K. Dahan J. Redon M.J. et al.Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer.Proc Natl Acad Sci USA. 2010; 107: 20471-20476Crossref PubMed Scopus (159) Google Scholar]. The authors profiled miR expression in human hepatoblastoma (HB) and human hepatocelluar carcinoma (HCC) and investigated the impact of altered miR expression on tumor biology. Overall the study underscores the value of miR expression changes for stratification of patients with both HB and HCC. HB is the most frequent pediatric liver cancer with clear differences in etiology and histopathology from HCC, the predominant form of adult liver cancer. The most notable difference is that HB develops in the absence of liver disease or viral infection, leading to the notion that HB might have a genetic or epigenetic origin. Indeed, the involvement of the Wnt/β-catenin pathway was shown by the high rate (50–90%) of mutations in CTNNB1 [[11]Koch A. Denkhaus D. Albrecht S. Leuschner I. von Schweinitz D. Pietsch T. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene.Cancer Res. 1999; 59: 269-273PubMed Google Scholar]. Buendia and her colleagues have also shown that interaction of Wnt/β-catenin and Myc signaling is critical in poorly differentiated aggressive HBs [[12]Cairo S. Armengol C. De Reyniès A. Wei Y. Thomas E. Renard C.A. et al.Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.Cancer Cell. 2008; 14: 471-484Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar]. The key findings of the current paper are the over-expression of the miR-371–3 cluster and a concomitant down-regulation of the miR-100/let-7a-2/miR-125b-1 cluster in undifferentiated aggressive HBs that mimics an ES cell expression profile. The involvement of MYC in regulating two critical miR clusters in the opposite manner was demonstrated by ChIP and Myc inhibition assays in hepatoma cells. Furthermore, the authors showed that over-expression of the miR-100/let-7a-2/miR-125b-1 cluster in Huh6 cells delayed tumor occurrence whereas simultaneous inhibition of miR-371–3 completely blocked tumor formation, suggesting that antagonistic interplay of the two miR clusters may decide cancer cell fate. From these data the authors conclude that the combined deregulation of the two miR clusters cooperated in modulating hepatic tumor phenotype, implicating stem cell-like regulation of Myc-dependent miRs in poorly differentiated HBs. Finally, the authors identified a four-miR signature representative of these clusters (i.e., miR-100, let-7a, miR-371, and miR-373) that efficiently stratified HB patients, and when applied to 241 HCCs, it identified invasive tumors with a poor prognosis. Based on these data the authors reached a central conclusion that Myc driven reprograming of miR expression patterns contributes to the aggressive phenotype of liver tumors originating from hepatic progenitor cells. Although fully justified for HB, the situation may be more complex for HCC. This is well illustrated by the considerably reduced power of the four-miR signature to separate the two survival classes (i.e., Cm1 and Cm2; Fig. 5 in the article) in HCC as compared to HB. The explanation for this difference may be due in part to the heterogeneous nature of HCC. The existence of combined hepatocellular-cholangiocarcinoma (CHC), a histopathologic intermediate form between HCC and cholangiocarcinoma (CC), suggests phenotypic overlap between these tumor types. This issue has been recently addressed by applying an integrative oncogenomic approach to address the clinical and functional implications of the overlapping phenotypes between HCC and CC [[13]Woo H.G. Lee J.H. Yoon J.H. Kim C.Y. Lee H.S. Jang J.J. et al.Identification of a cholangiocarcinoma-like gene expression trait in hepatocellular carcinoma.Cancer Res. 2010; 70: 3034Crossref PubMed Scopus (139) Google Scholar]. Gene expression profiling of human HCC, CHC, and CC, identified a novel HCC subtype, i.e., cholangiocarcinoma-like HCC (CLHCC), which expressed CC-like traits (CC signature). Similar to CC and CHC, CLHCC showed an aggressive phenotype with shorter recurrence-free and overall survival. In addition, CLHCC co-expressed embryonic stem cell-like expression traits (ES signature) suggesting derivation from bipotent hepatic progenitor cells. Comparison of CC signature with previous ES-like, hepatoblast-like, or proliferation-related expression traits revealed that the prognostic value of the CC signatures was independent of these signatures. These data emphasize the critical role of the cell of origin in HCC pathogenesis. The elegant work by Buendia and her colleagues has significantly advanced our current understanding of the pathogenesis of liver cancer. How and to what extent the interplay of MYC, miRs, and stemness participate in HCC pathogenesis and heterogeneity remains to be further explored. The underlying research reported in the study was funded by the NIH Institutes of Health