title: In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3-Mediated Apoptosis.
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 provedin vivoefficacy 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.
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy. francesca.fornari2@unibo.it laura.gramantieri@aosp.bo.it.|Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fornari
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pollutri
authors.affiliation: Center for Regenerative Medicine, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Patrizi
authors.affiliation: INSERM, UMR-1162, Functional Genomics of Solid Tumors, Paris, France.
authors.forename: Tiziana
authors.initials: T
authors.lastname: La Bella
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Marinelli
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Casadei Gardini
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Marisi
authors.affiliation: Department of Veterinary Medical Sciences, Bologna University, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Baron Toaldo
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Baglioni
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Salvatore
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Ferrara University, Ferrara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Callegari
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Baldassarre
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Galassi
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.|Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Giovannini
authors.affiliation: Department of Medical and Surgical Sciences, General and Transplant Surgery Unit, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cescon
authors.affiliation: Department of Medical and Surgical Sciences, General and Transplant Surgery Unit, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Ravaioli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Ferrara University, Ferrara, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy.|Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bolondi
authors.affiliation: Center for Applied Biomedical Research, St.Orsola-Malpighi University Hospital, Bologna, Italy. francesca.fornari2@unibo.it laura.gramantieri@aosp.bo.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Gramantieri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D053148:Caspase 3; D035683:MicroRNAs; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; C525709:MIR221, human