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Authors: Ellen V. Stevens, Natalie Banet, Cercina Onesto, Ana Plachco, Jamie K. Alan, Nana Nikolaishvili-Feinberg, Bentley R. Midkiff, Pei Fen Kuan, Jinsong Liu, C. Ryan Miller, Dominico Vigil, Lee M. Graves and Channing J. Der

Ellen V. Stevens

Department of Pharmacology; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Natalie Banet

Department of Pathology and Laboratory Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Cercina Onesto

Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Ana Plachco

Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Jamie K. Alan

Department of Pharmacology; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Nana Nikolaishvili-Feinberg

Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Bentley R. Midkiff

Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Pei Fen Kuan

Department of Biostatistics; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Jinsong Liu

Department of Pathology; The University of Texas MD Anderson Cancer Center; Houston, TX USA

C. Ryan Miller

Department of Pathology and Laboratory Medicine; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Dominico Vigil

Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Lee M. Graves

Department of Pharmacology; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Channing J. Der

Corresponding author: cjder@med.unc.edu
Department of Pharmacology; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA

Abstract:
Previous studies described functional roles for Rho GDP dissociation inhibitor 2 (RhoGDI2) in bladder, gastric and breast cancers. However, only limited expression and no functional analyses have been done for RhoGDI2 in ovarian cancer. We determined RhoGDI2 protein expression and function in ovarian cancer. First, western blot analysis was performed to determine the expression levels of RhoGDI2 in ovarian cells lines. RhoGDI2 but not RhoGDI1 protein expression levels varied widely in ovarian carcinoma cell lines, with elevated levels seen in Ras-transformed ovarian epithelial cells. Next, immunohistochemistry was performed to detect RhoGDI2 expression in patient samples of ovarian cysts and ovarian cancer with known histological subtype, stage, grade and outcome. RhoGDI2 protein was significantly overexpressed in high-grade compared to low-grade ovarian cancers, correlated with histological subtype, and did not correlate with stage of ovarian cancer nor between carcinomas and benign cysts. Unexpectedly, stable suppression of RhoGDI2 protein expression in HeyA8 ovarian cancer cells increased anchorage-independent growth and Matrigel invasion in vitro and in tail-vein lung colony metastatic growth in vivo. Finally, we found that RhoGDI2 stably-associated preferentially with Rac1 and suppression of RhoGDI2 expression resulted in decreased Rac1 activity and Rac-associated JNK and p38 mitogen-activated protein kinase signaling. RhoGDI2 antagonizes the invasive and metastatic phenotype of HeyA8 ovarian cancer cells. In summary, our results suggest significant cell context differences in RhoGDI2 function in cancer cell growth.

Received: June 15, 2011; Accepted: August 18, 2011

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