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

Oncogene volume 31, pages 4517–4526 (2012)Cite this article

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Abstract

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.

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Acknowledgements

We thank L Tamagnone, S Corso, MM Angioni and our colleagues for helpful discussions; C Manca for the preparation of rat samples and C Isella for statistical analysis; L Palmas for technical assistance. Work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC grants to SG, AC), Regione Piemonte (grant to SG) and MIUR (grants to SG, AC, GMLC, GDP).

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Author notes

  1. A Columbano and S Giordano: These authors equally contributed to the work.

Authors and Affiliations

  1. IRCC, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Torino, Italy

    A Petrelli, K Schernhuber, M Cargnelutti, C Migliore, E Ghiso & S Giordano

  2. Department of Toxicology, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy

    A Perra, G M Ledda-Columbano & A Columbano

  3. Department of Biomedical Sciences and Biotechnologies, Division of Biology and Genetics, School of Medicine, University of Brescia, Brescia, Italy

    A Salvi, S Barlati & G De Petro

  4. Department of Pathology, School of Medicine, University of Brescia, Brescia, Italy

    A Benetti

  5. Department of Medical and Surgical Sciences, Surgical Clinic, School of Medicine, University of Brescia, Brescia, Italy

    N Portolani

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  1. A Petrelli
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Correspondence to A Petrelli, A Columbano or S Giordano.

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Petrelli, A., Perra, A., Schernhuber, K. et al. Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression. Oncogene 31, 4517–4526 (2012). https://doi.org/10.1038/onc.2011.631

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