The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma

Daniela Pollutri, Clarissa Patrizi, Sara Marinelli, Catia Giovannini, Elena Trombetta, Ferdinando A. Giannone, Maurizio Baldassarre, Santina Quarta, Y. P. Vandewynckel, A. Vandierendonck, H. Van Vlierberghe, Laura Porretti, Massimo Negrini, Luigi Bolondi, Laura Gramantieri, Francesca Fornari

Research output: Contribution to journalArticle

Abstract

Hepatocellular carcinoma (HCC) represents the second cause of cancer-related mortality worldwide and is associated with poor prognosis, especially in patients not amenable for curative treatments. The multi-kinase inhibitor sorafenib represents the first-line treatment option for advanced HCC; nevertheless, its effectiveness is limited due to tumor heterogeneity as well as innate or acquired drug resistance, raising the need for new therapeutic strategies. MicroRNAs (miRNAs) involvement in treatment response as well as their safety and efficacy in preclinical models and clinical trials have been widely documented in the oncologic field, including HCC. Here, we identified miR-494 upregulation in a subgroup of human and rat HCCs with stem cell-like characteristics, as well as multiple epigenetic mechanisms involved in its aberrant expression in HCC cell lines and patients. Moreover, we identified p27, puma and pten among miR-494 targets, contributing to speed up cell cycle progression, enhance survival potential in stressful conditions and increase invasive and clonogenic capabilities. MiR-494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines and, in line, high miR-494 levels associated with decreased sorafenib response in two HCC animal models. A sorafenib-combined anti-miR-494-based strategy revealed an enhanced anti-tumor potential with respect to sorafenib-only treatment in our HCC rat model. In conclusion, our findings suggested miR-494 as a possible therapeutic target as well as a candidate biomarker for patient stratification in advanced HCC.

Original languageEnglish
Article number4
JournalCell Death and Disease
Volume9
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

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Hepatocellular Carcinoma
Stem Cells
Phenotype
Therapeutics
Puma
Cell Line
Second Primary Neoplasms
sorafenib
MicroRNAs
Drug Resistance
Epigenomics
Neoplasms
Cell Cycle
Phosphotransferases
Up-Regulation
Animal Models
Biomarkers
Clinical Trials
Safety
Survival

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma. / Pollutri, Daniela; Patrizi, Clarissa; Marinelli, Sara; Giovannini, Catia; Trombetta, Elena; Giannone, Ferdinando A.; Baldassarre, Maurizio; Quarta, Santina; Vandewynckel, Y. P.; Vandierendonck, A.; Van Vlierberghe, H.; Porretti, Laura; Negrini, Massimo; Bolondi, Luigi; Gramantieri, Laura; Fornari, Francesca.

In: Cell Death and Disease, Vol. 9, No. 1, 4, 01.01.2018.

Research output: Contribution to journalArticle

Pollutri, D, Patrizi, C, Marinelli, S, Giovannini, C, Trombetta, E, Giannone, FA, Baldassarre, M, Quarta, S, Vandewynckel, YP, Vandierendonck, A, Van Vlierberghe, H, Porretti, L, Negrini, M, Bolondi, L, Gramantieri, L & Fornari, F 2018, 'The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma', Cell Death and Disease, vol. 9, no. 1, 4. https://doi.org/10.1038/s41419-017-0076-6
Pollutri, Daniela ; Patrizi, Clarissa ; Marinelli, Sara ; Giovannini, Catia ; Trombetta, Elena ; Giannone, Ferdinando A. ; Baldassarre, Maurizio ; Quarta, Santina ; Vandewynckel, Y. P. ; Vandierendonck, A. ; Van Vlierberghe, H. ; Porretti, Laura ; Negrini, Massimo ; Bolondi, Luigi ; Gramantieri, Laura ; Fornari, Francesca. / The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma. In: Cell Death and Disease. 2018 ; Vol. 9, No. 1.
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