In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3–mediated apoptosis

Francesca Fornari, Daniela Pollutri, Clarissa Patrizi, Tiziana La Bella, Sara Marinelli, Andrea Casadei Gardini, Giorgia Marisi, M. Baron Toaldo, Michele Baglioni, Veronica Salvatore, Elisa Callegari, Maurizio Baldassarre, Marzia Galassi, Catia Giovannini, Matteo Cescon, Matteo Ravaioli, Massimo Negrini, Luigi Bolondi, Laura Gramantieri

Research output: Contribution to journalArticle

Abstract

Purpose: The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved in vivo efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC. Experimental Design: A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC. Results: MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients. Conclusions: MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance.

Original languageEnglish
Pages (from-to)3953-3965
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
Publication statusPublished - Jul 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fornari, F., Pollutri, D., Patrizi, C., La Bella, T., Marinelli, S., Casadei Gardini, A., Marisi, G., Baron Toaldo, M., Baglioni, M., Salvatore, V., Callegari, E., Baldassarre, M., Galassi, M., Giovannini, C., Cescon, M., Ravaioli, M., Negrini, M., Bolondi, L., & Gramantieri, L. (2017). In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3–mediated apoptosis. Clinical Cancer Research, 23(14), 3953-3965. https://doi.org/10.1158/1078-0432.CCR-16-1464