miR-579-3p Controls Hepatocellular Carcinoma Formation by Regulating the Phosphoinositide 3-Kinase–Protein Kinase B Pathway in Chronically Inflamed Liver

Cristina Quintavalle, Nathalie Meyer-Schaller, Stephanie Roessler, Diego Calabrese, Romina Marone, Tobias Riedl, Silvia Picco-Rey, Orestis A. Panagiotou, Sarp Uzun, Salvatore Piscuoglio, Tuyana Boldanova, Chaoran B. Bian, David Semela, Wolfram Jochum, Gieri Cathomas, Kirsten D. Mertz, Joachim Diebold, Luca Mazzucchelli, Viktor H. Koelzer, Achim WeberThomas Decaens, Luigi M. Terracciano, Mathias Heikenwalder, Yujin Hoshida, Jesper B. Andersen, Snorri S. Thorgeirsson, Matthias S. Matter

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic liver inflammation causes continuous liver damage with progressive liver fibrosis and cirrhosis, which may eventually lead to hepatocellular carcinoma (HCC). Whereas the 10-year incidence for HCC in patients with cirrhosis is approximately 20%, many of these patients remain tumor free for their entire lives. Clarifying the mechanisms that define the various outcomes of chronic liver inflammation is a key aspect in HCC research. In addition to a wide variety of contributing factors, microRNAs (miRNAs) have also been shown to be engaged in promoting liver cancer. Therefore, we wanted to characterize miRNAs that are involved in the development of HCC, and we designed a longitudinal study with formalin-fixed and paraffin-embedded liver biopsy samples from several pathology institutes from Switzerland. We examined the miRNA expression by nCounterNanostring technology in matched nontumoral liver tissue from patients developing HCC (n = 23) before and after HCC formation in the same patient. Patients with cirrhosis (n = 26) remaining tumor free within a similar time frame served as a control cohort. Comparison of the two cohorts revealed that liver tissue from patients developing HCC displayed a down-regulation of miR-579-3p as an early step in HCC development, which was further confirmed in a validation cohort. Correlation with messenger RNA expression profiles further revealed that miR-579-3p directly attenuated phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) expression and consequently protein kinase B (AKT) and phosphorylated AKT. In vitro experiments and the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology confirmed that miR-579-3p controlled cell proliferation and cell migration of liver cancer cell lines. Conclusion: Liver tissues from patients developing HCC revealed changes in miRNA expression. miR-579-3p was identified as a novel tumor suppressor regulating phosphoinositide 3-kinase–AKT signaling at the early stages of HCC development.

Original languageEnglish (US)
JournalHepatology Communications
DOIs
StateAccepted/In press - 2022
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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