Abstract 1745: Role and mechanism of MUC16 in the pathogenesis of pancreatic cancer.

Abstract

Abstract Background: MUC16/ CA125 is a high-molecular weight O-glycosylated protein that has been shown to be dysregulated and aberrantly expressed during the progression of several malignant conditions including pancreatic cancer (PC). MUC16 is the gold standard tumor marker used in clinics for detecting ovarian cancer. CA125 levels have been shown to be elevated in PC but its functional significance in PC remains elusive. Hence we hypothesize that MUC16 plays an important role in the proliferation and metastasis of PC. Materials and methods: MUC16 expression was analyzed in 14 human PC cell lines and stable knockdown clones of MUC16 were established in Capan1 and Colo357 PC cell lines by retroviral transfection using the shRNA construct (pSUPER-Retro-MUC16-sh). Growth kinetics, motility and tumorogenicity assays were done on both MUC16 knocked down cells and scramble cells. In addition we also analyzed the expression of Muc16 during PC progression using the spontaneous mouse model (KrasG12D;Pdx1-Cre and KrasG12D;Pdx1-Cre; Trp53R172H) to identify the role of Muc16 in facilitating PC progression. Results: MUC16 is not expressed in the normal pancreatic ducts or acini; however, a strong expression is observed in PC tissues. Further a similar observation was obtained in the spontaneous mouse model wherein expression of Muc16 increased in tandem with PC progression. PC cells with stably silenced MUC16 exhibited significantly decreased proliferation, motility (in vitro), tumorigenicity and metastasis (in vivo) when compared to scrambled RNA transfected cells. In addition, MUC16 knockdown cells accumulated in the G1/S phase of the cell cycle indicating that MUC16 might play a role in cell cycle regulation. Western blot analysis of MUC16 knockdown cells with Cyclin E, p21 and p27 showed a decrease in their expression indicating that MUC16 could be playing an important role during PC cell cycle progression. Conclusion: Our results show that MUC16 expression is aberrantly upregulated in PC tissues and plays a key role in the proliferation and metastasis of PC cells as inferred from the various in vitro and in vivo assays. Further MUC16 may be play a significant in facilitating cell cycle progression as Cyclin E, p21 and p27 levels were altered when MUC16 was knocked down. In conclusion, our results reveal that MUC16 is differentially expressed in PC and could be a potential player facilitating distant metastasis in PC. Further studies need to be done to determine the specific role of MUC16 in the metastasis of PC. Citation Format: Dhanya Haridas, Imayavaramban Lakshmanan, Moorthy P. Ponnusamy, Satyanarayana Rachagani, Srustidhar Das, Sushil Kumar, Surinder K. Batra. Role and mechanism of MUC16 in the pathogenesis of pancreatic cancer. [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 1745. doi:10.1158/1538-7445.AM2013-1745