Short-form Ron is a novel determinant of ovarian cancer initiation and progression
Katherine M. Moxley1, Luyao Wang2, Alana L. Welm3,*, and Magdalena Bieniasz2,*
1 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
2 Functional and Chemical Genomics Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
3 Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA
* Co-senior authors
Correspondence:
Magdalena Bieniasz, email:
Correspondence:
Alana Welm, email:
Keywords: sfRon, high-grade serous ovarian cancer, PDK1, ovarian cancer, PI3K
Received: May 05, 2016 Accepted: July 11, 2016 Published: July 13, 2016
Abstract
Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment.
