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.

Fornari, F., Pollutri, D., Patrizi, C., LA BELLA, T., Marinelli, S., Casadei Gardini, A., et al. (2017). In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3â mediated apoptosis. CLINICAL CANCER RESEARCH, 23(14), 3953-3965 [10.1158/1078-0432.CCR-16-1464].

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

Fornari, Francesca
;
Pollutri, Daniela;PATRIZI, CLARISSA;LA BELLA, TIZIANA;Marinelli, Sara;Baron Toaldo, M.;Baglioni, Michele;Salvatore, Veronica;Baldassarre, Maurizio;Galassi, Marzia;Giovannini, Catia;Cescon, Matteo;Ravaioli, Matteo;Bolondi, Luigi;Gramantieri, Laura
2017

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.
2017
Fornari, F., Pollutri, D., Patrizi, C., LA BELLA, T., Marinelli, S., Casadei Gardini, A., et al. (2017). In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3â mediated apoptosis. CLINICAL CANCER RESEARCH, 23(14), 3953-3965 [10.1158/1078-0432.CCR-16-1464].
Fornari, Francesca; Pollutri, Daniela; Patrizi, Clarissa; LA BELLA, Tiziana; Marinelli, Sara; Casadei Gardini, Andrea; Marisi, Giorgia; BARON TOALDO, ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/612183
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