Abstract 5180: MUC4 mucin upregulates N-cadherin: A novel mechanism for human ovarian tumor metastasis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.5180-5180
• Main Authors: Ponnusamy, Moorthy Palanimuthu, Lakshmanan, Imayavaramban, Jain, Maneesh, Batra, Surinder K.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-5180

The human MUC4 protein is a high molecular weight transmembrane glycoprotein which is over-expressed in ovarian tumors and plays a role in increasing the cellular motility of the ovarian cancer cells. Previous reports have indicated that gain of expression of N-cadherin in tumor cells is associated with increased motility and metastasis. We hypothesize that MUC4 upregulates N-cadherin and plays a major role in metastasis of ovarian cancer. The aim of the present study was to analyze the mechanism of MUC4 induced cellular motility, invasion and metastasis in ovarian cancer cells. For this we have used a MUC4 gene construct (entire coding sequence along with 10% of the central tandem repeat region) for ectopic expression to determine the metastatic function of MUC4 in human ovarian cancer cells (SKOV3). Interestingly, we observed that N-cadherin was up-regulated in MUC4 overexpressing ovarian cancer cells (SKOV3-MUC4) compared to control (vector transfected) cells. We further discovered that N-cadherin upstream pathways such as FAK, MKK7, JNK and c-Jun are activated in the MUC4 expressing SKOV3 cells. Additionally, inhibition of pFAK led to the downregulation of N-cadherin by inhibiting the activation of MKK7, JNK and c-Jun in MUC4 overexpressing SKOV3 cells. On other hand, knockdown of N-cadherin decreased the activation of ERK, AKT and MMP9 in the MUC4 expressing SKOV3 cells. Inhibition of pFAK, pJNK and knockdown of N-cadherin in the MUC4 overexpressing cells further led to a significant decrease in cellular motility. Upon tumorigenisis and metastasis analysis with NOD-SCID mice, the SKOV3-MUC4 cells produced significantly larger tumors and demonstrated a higher incidence of metastasis to distant organs (peritoneal wall, colon, intestine, stomach, lymph nodes, liver and diaphragm) than the SKOV3-vector cells. Taken together, our result suggests that MUC4 mediated upregulation of N-cadherin plays a major role in promoting the metastatic property of ovarian cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5180.