Expression and Functions of Transmembrane Mucin MUC13 in Ovarian Cancer

¹Cancer Biology Research Center, Sanford Research/University of South Dakota; Departments of ²Obstetrics and Gynecology and ³Laboratory Medicine and Pathology, Sanford School of Medicine, Sioux Falls, South Dakota; ⁴University of Tokyo, Tokyo, Japan; ⁵Department of Mathematical Science, University of South Dakota, Vermillion, South Dakota; and ⁶Institute for Molecular Virology, Saint Louis University, St. Louis, Missouri

^* To whom correspondence should be addressed. E-mail: subhash.chauhan{at}usd.edu.

	Abstract

MUC13, a transmembrane mucin, is normally expressed in gastrointestinal and airway epithelium. Its aberrant expression has been correlated with gastric colon and cancer. However, the expression and functions of MUC13 in ovarian cancer are unknown. In the present study, the expression profile and functions of MUC13 were analyzed to elucidate its potential role in ovarian cancer diagnosis and pathogenesis. A recently generated monoclonal antibody (clone PPZ0020) was used to determine the expression profile of MUC13 by immunohistochemistry using ovarian cancer tissue microarrays and 56 additional epithelial ovarian cancer (EOC) samples. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with the normal ovary/benign tissues. Among all ovarian cancer types, MUC13 expression was specifically present in EOC. For the functional analyses, a full-length MUC13 gene cloned in pcDNA3.1 was expressed in a MUC13 null ovarian cancer cell line, SKOV-3. Here, we show that the exogenous MUC13 expression induced morphologic changes, including scattering of cells. These changes were abrogated through c-Jun NH₂ kinase (JNK) chemical inhibitor (SP600125) or JNK2 siRNA. Additionally, a marked reduction in cell-cell adhesion and significant (P < 0.05) increases in cell motility, proliferation, and tumorigenesis in a xenograft mouse model system were observed upon exogenous MUC13 expression. These cellular characteristics were correlated with up-regulation of HER2, p21-activated kinase 1, and p38 protein expression. Our findings show the aberrant expression of MUC13 in ovarian cancer and that its expression alters the cellular characteristics of SKOV-3 cells. This implies a significant role of MUC13 in ovarian cancer. [Cancer Res 2009;69(3):765–74]

Key Words: MUC13, mucin, ovarian cancer, cell migration, cell proliferation

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