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Clin Cancer Res. 2017 Jul 15;23(14):3953-3965. doi: 10.1158/1078-0432.CCR-16-1464. Epub 2017 Jan 17.

In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3-Mediated Apoptosis.

Author information

1
Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy. francesca.fornari2@unibo.it laura.gramantieri@aosp.bo.it.
2
Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
3
Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.
4
Center for Regenerative Medicine, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
5
INSERM, UMR-1162, Functional Genomics of Solid Tumors, Paris, France.
6
Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
7
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
8
Department of Veterinary Medical Sciences, Bologna University, Bologna, Italy.
9
Department of Morphology, Surgery and Experimental Medicine, Ferrara University, Ferrara, Italy.
10
Department of Medical and Surgical Sciences, General and Transplant Surgery Unit, St. Orsola-Malpighi University Hospital, Bologna, Italy.

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. Clin Cancer Res; 23(14); 3953-65. ©2017 AACR.

PMID:
28096271
DOI:
10.1158/1078-0432.CCR-16-1464
[Indexed for MEDLINE]
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