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

John K Chan; Tuyen K Kiet; Kevin Blansit; Rashmi Ramasubbaiah; Joan F Hilton; Daniel S Kapp; Daniela Matei

doi:10.1016/j.ygyno.2014.03.564

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

Gynecol Oncol. 2014 Jun;133(3):568-74. doi: 10.1016/j.ygyno.2014.03.564. Epub 2014 Mar 25.

Authors

John K Chan¹, Tuyen K Kiet², Kevin Blansit³, Rashmi Ramasubbaiah⁴, Joan F Hilton⁵, Daniel S Kapp⁶, Daniela Matei⁴

Affiliations

¹ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA; Palo Alto Medical Foundation Research Institute, 795 El Camino Real, Palo Alto, CA 94301, USA. Electronic address: chanjohn@obgyn.ucsf.edu.
² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA.
³ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA; Palo Alto Medical Foundation Research Institute, 795 El Camino Real, Palo Alto, CA 94301, USA.
⁴ Department of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, 185 Berry Street, Box 0560, San Francisco, CA 94143, U S A.
⁵ Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 980 W. Walnut Street, R3 C218D, Indianapolis, IN 46202, U S A.
⁶ Department of Radiation Oncology, Stanford University School of Medicine, Stanford Cancer Center, 875 Blake Wilbur Drive, Stanford, CA 94305, USA.

PMID: 24680769
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. 4.2months; 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. 4.2months, p=0.04 for high vs. low ALCAM; 7.9 vs. 2.3months, 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.

Keywords: Anti-angiogenic therapy; MiR-378; MicroRNA; Ovarian cancer; Survival.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / therapeutic use*
Antibodies, Monoclonal, Humanized / therapeutic use*
Bevacizumab
Biomarkers, Tumor
Cell Line, Tumor
Disease-Free Survival
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Humans
Kaplan-Meier Estimate
MicroRNAs / genetics*
Middle Aged
Multivariate Analysis
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / genetics
Prognosis
Proportional Hazards Models
Reverse Transcriptase Polymerase Chain Reaction
Treatment Outcome

Substances

Angiogenesis Inhibitors
Antibodies, Monoclonal, Humanized
Biomarkers, Tumor
MIRN378 microRNA, human
MicroRNAs
Bevacizumab