Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression

• Published in: Oncogene Vol. 31; no. 42; pp. 4517 - 4526
• Main Authors: Petrelli, A, Perra, A, Schernhuber, K, Cargnelutti, M, Salvi, A, Migliore, C, Ghiso, E, Benetti, A, Barlati, S, Ledda-Columbano, G M, Portolani, N, De Petro, G, Columbano, A, Giordano, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.10.2012; Nature Publishing Group
• Subjects: 631/208/199; 631/337/384/331; 631/67/1504/1610; 692/420/755; Adenoma; Agar; Animal models; Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation; Colonies; Development and progression; Disease Models, Animal; Disease Progression; Down-Regulation; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic regulation; Hepatocellular carcinoma; Hepatocytes; Hepatoma; Human Genetics; Humans; Immunohistochemistry; Internal Medicine; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Medicine; Medicine & Public Health; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Neoplasm Staging; Oncology; original-article; Pathogenesis; Physiological aspects; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rats; Ribonucleic acid; RNA; Tumors; Italy; miRNA; HCC; hepatocarcinogenesis; animal model; PLK1
• DOI: 10.1038/onc.2011.631
• ISSN: 0950-9232

MicroRNAs (miRNAs) have an important role in a wide range of physiological and pathological processes, and their dysregulation has been reported to affect the development and progression of cancers, including hepatocellular carcinoma (HCC). However, in the plethora of dysregulated miRNAs, it is largely unknown which of them have a causative role in the hepatocarcinogenic process. In the present study, we first aimed to determine changes in the expression profile of miRNAs in human HCCs and to compare them with liver tumors generated in a rat model of chemically induced HCC. We found that members of the miR-100 family (miR-100, miR-99a) were downregulated in human HCCs; a similar downregulation was also observed in rat HCCs. Their reduction was paralleled by an increased expression of polo like kinase 1 (PLK1), a target of these miRNAs. The introduction of miR-100 in HCC cells impaired their growth ability and their capability to form colonies in soft agar. Next, we aimed at investigating, in the same animal model, if dysregulation of miR-100 and PLK1 is an early or late event along the multistep process of hepatocarcinogenesis. The obtained results showed that miR-100 downregulation (i) is already evident in very early preneoplastic lesions generated 9 weeks after carcinogenic treatment; (ii) is also observed in adenomas and early HCCs; and (iii) is not simply a marker of proliferating hepatocytes. To our knowledge, this is the first work unveiling the role of a miRNA family along HCC progression.