MiR-378 as a biomarker for response to anti-angiogenic treatment in ovarian cancer

• Published in: Gynecologic oncology 2014-06, Vol.133 (3), p.568-574
• Main Authors: Chan, John K, Kiet, Tuyen K, Blansit, Kevin, Ramasubbaiah, Rashmi, Hilton, Joan F, Kapp, Daniel S, Matei, Daniela
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - therapeutic use; Anti-angiogenic therapy; Antibodies, Monoclonal, Humanized - therapeutic use; Bevacizumab; Biomarkers, Tumor; Cell Line, Tumor; Disease-Free Survival; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hematology, Oncology and Palliative Medicine; Humans; Kaplan-Meier Estimate; MicroRNA; MicroRNAs - genetics; Middle Aged; MiR-378; Multivariate Analysis; Obstetrics and Gynecology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Prognosis; Proportional Hazards Models; Reverse Transcriptase Polymerase Chain Reaction; Survival; Treatment Outcome
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2014.03.564

Abstract Objective To determine the role of miR-378 as a biomarker for anti-angiogenic therapy response in ovarian cancer. Methods Expression of miR-378 was analyzed in ovarian cancer cell lines and human tumors vs. normal ovarian epithelial cells by qRT-PCR. After miR-378 transfection in SKOV3 cells, dysregulated genes were identified using microarray. Data from The Cancer Genome Atlas (TCGA) was utilized to correlate miR-378 expression with progression-free survival (PFS) among patients treated with anti-angiogenic therapy by using Kaplan–Meier and Cox proportional hazards. Results MiR-378 was overexpressed in ovarian cancer cells and tumors vs. normal ovarian epithelial cells. Overexpressing miR-378 in ovarian cancer cells altered expression of genes associated with angiogenesis (ALCAM, EHD1, ELK3, TLN1), apoptosis (RPN2, HIPK3), and cell cycle regulation (SWAP-70, LSM14A, RDX). In the TCGA dataset, low vs. high miR-378 expression was associated with longer PFS in a subset of patients with recurrent ovarian cancer treated with bevacizumab (9.2 vs. 4.2 months; p = 0.04). On multivariate analysis, miR-378 expression was an independent predictor for PFS after anti-angiogenic treatment (HR = 2.04, 95% CI: 1.12–3.72; p = 0.02). Furthermore, expression levels of two miR-378 targets (ALCAM and EHD1) were associated with PFS in this subgroup of patients who received anti-angiogenic therapy (9.4 vs. 4.2 months, p = 0.04 for high vs. low ALCAM; 7.9 vs. 2.3 months, p < 0.01 for low vs. high EHD1). Conclusions Our data suggest that miR-378 is overexpressed in ovarian cancer cells and tumors vs. normal ovarian epithelial cells. MiR-378 and its downstream targets may serve as markers for response to anti-angiogenic therapy.