Epithelial ovarian carcinoma is the most common cause of death among gynecologic malignancies in the United States. In the U.S., more than 21,000 women will be diagnosed with ovarian cancer and about 15,000 women will die of the disease this year alone. Although migration and invasion play key roles in tumor progression, the specific molecular events leading to dissemination of ovarian tumor cells have not been well delineated. Tight junctions are an integral component of epithelial junction complexes, which play a vital role in maintaining epithelial integrity and cell polarity. Disruption of tight junctions is a hallmark of epithelial cancer development and malignant progression; specifically decreased claudin-1 expression has been associated with progression to tumor malignancy. Herein, we investigate the mechanism by which claudin-1 expression is regulated via activation of the TGFβ and RON tyrosine kinase receptor signaling pathways. We propose that claudin-1 expression is regulated by the activation of the TGFβ signaling pathway (dysregulated in ovarian carcinomas), particularly SnoN/SkiL, a key TGFβ co-repressor. In ovarian carcinoma cells, we observed that treatment with TGFβ and MSP1 led to a marked reduction in claudin-1 protein expression. Further, we not only noted that siRNA targeting RON led to upregulated claudin-1 mRNA and protein expression, but similar changes in mRNA and proteins of claudin-1 were observed with SnoN and β-catenin knockdown. Strikingly, with β-catenin knockdown, SnoN levels were notably decreased suggesting that β-catenin could potentially regulate SnoN expression. Collectively, our results demonstrate that claudin-1 expression is regulated by the transcriptional regulators β-catenin and SnoN. Since identification of novel biomarkers could be beneficial in diagnosis, prognosis and prediction of patient outcomes, these observations regarding the cellular events underlying regulation of claudin-1 expression are of translational potential.
Scholar Commons Citation
Karim, Saya, "Regulation of Claudin-1 Expression Via Activation of Ron Tyrosine Kinase and Transforming Growth Factor-Beta Signaling Pathways in Ovarian Carcinoma" (2010). Outstanding Honors Theses. 40.