Deregulation of microRNAs expression occurs in stages of multistep hepatocarcinogenesis: Why is it different?
Authors: Guohong Cai, Ya Liu, Wen Yin
Journal: Journal of Hepatology (2012)

Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesisJournal of HepatologyVol. 54Issue 6PreviewDeregulation of microRNAs (miRNAs) plays an important role in human carcinogenesis. However, miRNA deregulation in the pre-malignant lesions and expression changes during multistep hepatocarcinogenesis remain elusive. Full-Text PDF Reply to: “Deregulation of microRNAs expression occurs in stages of multistep hepatocarcinogenesis: Why is it different?”Journal of HepatologyVol. 56Issue 6PreviewYin et al. drew attention to the differences between the findings on miR-221, miR-21 and miR-122 deregulation in hepatocarcinogenesis reported in our recent study [1] and others [2–4]. Yin et al. further speculated that the inconsistence of the findings among these reports might be due to different risk factors for HCC and called for further investigations on this subject. Full-Text PDF Open Access HBV is a major cause of acute and chronic liver infection, and can lead to hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) [[1]Seeger C. Mason W.S. Hepatitis B virus biology.Microbiol Mol Biol Rev. 2000; 64: 51-68Crossref PubMed Scopus (1223) Google Scholar], which is the fifth most common cancer and the third leading cause of cancer death worldwide. More than 80% of HCC patients are in developing countries, especially in Southeast Asia and sub-Saharan Africa. However, the incidence of HCC has been rising in Western countries in recent years [[2]El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4514) Google Scholar]. The current standard of care and therapy for patients with advanced HCC are not satisfactory. Surgical resection or liver transplantation remains the most effective treatment options for HCC, but few patients are fortunate to get the treatment, for all kinds of reasons. Therefore, the analysis of the molecular mechanisms of oncogenesis is badly needed to uncover novel targets for specific systemic therapy and to discover novel biomarkers for early diagnosis of HCC. MicroRNAs (miRNAs), which are endogenous, small non-coding RNAs consisting of 20–25 nucleotides, have been shown to play important roles in various cellular and physiological processes, including cellular development, apoptosis, proliferation, and differentiation [3Dalmay T. MicroRNAs and cancer.J Intern Med. 2008; 263: 366-375Crossref PubMed Scopus (116) Google Scholar, 4Chen C.Z. Li L. Lodish H.F. Bartel D.P. MicroRNAs modulate hematopoietic lineage differentiation.Science. 2004; 303: 83-86Crossref PubMed Scopus (2804) Google Scholar]. Typically, they modulate gene expression by regulating the mRNA at a posttranscriptional stage, base-pairing with sequences in the 3′-untranslated region [3Dalmay T. MicroRNAs and cancer.J Intern Med. 2008; 263: 366-375Crossref PubMed Scopus (116) Google Scholar, 5Lau N.C. Lim L.P. Weinstein E.G. Bartel D.P. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans.Science. 2001; 294: 858-862Crossref PubMed Scopus (2697) Google Scholar]. There are currently 940 identifiable human miRNAs (The miRBase Sequence Database-Release ver. 15.0), which can recognize hundreds of target genes with incomplete complementarity and over one third of human genes appear to be conserved miRNA targets [[6]Zamore P.D. Haley B. Ribo-gnome: the big world of small RNAs.Science. 2005; 309: 1519-1524Crossref PubMed Scopus (1132) Google Scholar]. Recent evidence clearly shows that deregulation of miRNAs may contribute to aberrant activation of oncogenes and inactivation of tumor suppressor genes in human carcinogenesis. Several miRNAs have been linked to the initiation and progression of human cancers, including HBV-associated HCC [7Gao P. Wong C.L. Tung E.K. Lee J.M. Wong C.M. Ng I.O. Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis.J Hepatol. 2011; 54: 1177-1184Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 8Pineau P. Voliniab S. McJunkinc K. Marchioa A. Battistone C. Terrisf B. et al.MiR-221 overexpression contributes to liver tumorigenesis.Proc Natl Acad Sci USA. 2010; 107: 264-269Crossref PubMed Scopus (648) Google Scholar, 9Kutay H. Bai S. Datta J. Motiwala T. Pogribny I. Frankel W. et al.Downregulation of miR-122 in the rodent and human hepatocellular carcinomas.J Cell Biochem. 2006; 99: 671-678Crossref PubMed Scopus (544) Google Scholar, 10Connolly E. Melegari M. Landgraf P. Tchaikovskaya T. Tennant B.C. Slagle B.L. et al.Elevated expression of the miR-17-92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype.Am J Pathol. 2008; 173: 856-864Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar]. Thus, great efforts have been put on miRNA mimetics and anti-sense miRNA as potential therapeutics for hepatocellular carcinoma, due to their stability and predominant uptake by the liver. In the study by Gao et al. [[7]Gao P. Wong C.L. Tung E.K. Lee J.M. Wong C.M. Ng I.O. Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis.J Hepatol. 2011; 54: 1177-1184Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar], a panel of seven miRNAs (miR-10b, miR-21, miR-122, miR-145, miR-199b, miR-221, and miR-224) was selected to examine miRNA deregulation during early stages of hepatocarcinogenesis. Among these miRNAs, only miR-145, miR-199b, and miR-224 were found to be significantly deregulated during the multistep hepatocarcinogenesis. While other miRNAs’ expression changes seldom reached statistically significant levels among non-tumorous livers, dysplastic nodules and small HCC, after Bonferroni correction for multiple comparison tests [[7]Gao P. Wong C.L. Tung E.K. Lee J.M. Wong C.M. Ng I.O. Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis.J Hepatol. 2011; 54: 1177-1184Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar]. This conclusion was quite different from other study results. Pineau et al. concluded that among the miRNAs present in the progression signature, miR-221 was capable of stimulating tumor growth in vivo possibly through p27 and/or DDIT4 downregulation [[8]Pineau P. Voliniab S. McJunkinc K. Marchioa A. Battistone C. Terrisf B. et al.MiR-221 overexpression contributes to liver tumorigenesis.Proc Natl Acad Sci USA. 2010; 107: 264-269Crossref PubMed Scopus (648) Google Scholar]. The findings of Kutay et al. suggested that miR-122 downregulation was associated with hepatocarcinogenesis and could be a potential biomarker for liver cancer [[9]Kutay H. Bai S. Datta J. Motiwala T. Pogribny I. Frankel W. et al.Downregulation of miR-122 in the rodent and human hepatocellular carcinomas.J Cell Biochem. 2006; 99: 671-678Crossref PubMed Scopus (544) Google Scholar]. Connolly et al. initial analysis of cirrhotic livers suggested that upregulation of miR-17-92 and miR-21 occurred in pre-cancerous stages of liver disease [[10]Connolly E. Melegari M. Landgraf P. Tchaikovskaya T. Tennant B.C. Slagle B.L. et al.Elevated expression of the miR-17-92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype.Am J Pathol. 2008; 173: 856-864Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar]. Then, which conclusion is more convincing? And what makes them into controversies? Despite the difference in the methods used by the researchers, the development of hepatocellular carcinoma in individuals with chronic hepatitis B is a multistage, multifactorial process including the interaction between host and environmental factors [[11]Chen C.J. Chen D.S. Interaction of hepatitis B virus, chemical carcinogen, and genetic susceptibility: multistage hepatocarcinogenesis with multifactorial etiology.Hepatology. 2002; 36: 1046-1049Crossref PubMed Scopus (108) Google Scholar]. Risk factors for chronic HBV-related hepatocellular carcinoma include HBV DNA level, sex, age, cigarette smoking, alcohol consumption, chemical carcinogens, hormonal factors, and genetic susceptibility [[12]Chen C.J. Yu M.W. Liaw Y.F. Epidemiological characteristics and risk factors of hepatocellular carcinoma.J Gastroenterol Hepatol. 1997; 12: S294-S308Crossref PubMed Scopus (458) Google Scholar]. In a previous study, Zhang et al. [[13]Zhang Z.Z. Liu X. Wang D.Q. Teng M.K. Niu L.W. Huang A.L. et al.Hepatitis B virus and hepatocellular carcinoma at the miRNA level.World J Gastroenterol. 2011; 17: 3353-3358Crossref PubMed Scopus (59) Google Scholar] demonstrated that perturbations of miRNA expression during HBV infection were significantly correlated with those in HCC, and that aberrant expression of miR-199a, miR-199a∗, miR-200a, and miR-200b was associated with liver fibrosis progression. In addition, the work by Liu et al. [[14]Liu W.H. Yeh S.H. Lu C.C. Yu S.L. Chen H.Y. Lin C.Y. et al.MicroRNA-18a prevents estrogen receptor expression, promoting proliferation of hepatocellular carcinoma cells.Gastroenterology. 2009; 136: 683-693Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar] suggested that microRNA-18a prevented estrogen receptor expression, promoting proliferation of hepatocellular carcinoma cells, which could be a mechanism explaining the sex disparity observed in HCC. However, the relationship between miRNA expression and other risk factors for chronic HBV-related HCC remains elusive. In the past studies, scientists paid most of their attention on the miRNA expression changes during the process of HCC, without taking other risk factors for chronic HBV-related HCC into consideration. Even though more and more miRNAs are being reported to be frequently deregulated in human cancers and may play a role in liver carcinogenesis, it is difficult to judge which result is more convincing. Altered miRNA expression has been clearly linked to liver cancer, but the molecular mechanisms by which miRNA modulates hepatocarcinogenesis are still unknown. The reasons for their controversial study results are complex; we think lack of consideration of risk factors for chronic HBV-related HCC in these studies may be one of the key reasons. In summary, well designed and systematic studies are still needed to clarify the molecular mechanism that leads to deregulation of miRNA expression in HBV-associated multistep hepatocarcinogenesis. Incorporating HBV DNA level, sex, age, cigarette smoking, alcohol consumption, chemical carcinogens, hormonal factors, and genetic susceptibility when investigating the relationship between deregulation of miRNA expression and HCC may be helpful in resolving the controversies. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.