Background: Lung cancer is the most common cause of cancer related death in the world. The 5-year survival of lung cancer patients is a dismal 15%. MUC16 is a very high molecular weight glycoprotein with 22,152 amino acid residues in its protein sequence. According to Oncomine data, MUC16 is highly overexpressed in lung cancer particularly Non Small Cell Lung Cancer cell [NSCLC]. MUC16 is a well-established tumor marker in ovarian cancer but its functional and mechanistic role is not well understood. The Testis Specific Y-Like Protein (TSPYL5), which is also overexpressed in lung carcinoma (68%) and it has been suggested that overexpression of TSPYL5 induces cancer cell growth by suppressing p53 activity in terms. We evaluated the interplay between MUC16 and TSPYL5 in lung carcinogenesis.

Materials and Methods: Endogenously expressed MUC16 was stably knocked down using a MUC16 shRNA construct (pSUPER-Retro-MUC16-sh) in H292 and H827 lung cancer cells by stable transfection method. The cells were treated with cisplatin to investigate the role of MUC16 and TSPYL5 on chemoresistance in lung cancer cells and its role in p53 degradation.

Results: MUC16 is overexpressed in lung cancer while it is absent in normal lung tissues by immunohistochemistry analysis. Specifically MUC16 is highly observed in Stage III of lung carcinoma than other stages and metastatic sites as well. Significant expression of MUC16 was observed in NSCLC derived cell lines (H292 and H827) that express p53 (wild type). On knocking down MUC16 in H292 cells, a decrease in proliferation and an increase in the percentage of apoptotic cells were observed in comparison to vector control cells (by FACs). MUC16 knockdown in H292 cell lines decreased the motility and invasion compared to the MUC16 expressing control cells. Our microarray data suggest that multiple cancer-related genes including TSPYL5, CXCL1, CXCL2, CCL20, and IL8 are down-regulated in MUC16 knockdown cells. TSPYL5 suppresses p53 activity and thereby mediates cancer cell proliferation. Cisplatin treatment in H292 and H827 cells resulted in decreased expression of MUC16 and TSPYL5, and increased expression of p53. This indicates that MUC16 overexpression upregulates TSPYL5, which may suppresses the p53 activity thereby inducing lung cancer cell proliferation and making the cells insensitive to various cytotoxic agents.

Conclusion: MUC16 may play a significant role in lung cancer cell proliferation through the upregulation of TSPYL5 which in turn control p53 activity.

Citation Format: Imayavaramban Lakshmanan, Prabin D. Majhi, Moorthy P. Ponnusamy, Srustidhar Das, Parthasarathy Seshacharyulu, Dhanya Haridas, Surinder K. Batra, Apar Ganti. MUC16 upregulates TSPYL5 gene and mediates Lung cancer cell proliferation by suppressing p53 activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1760. doi:10.1158/1538-7445.AM2013-1760