Mucin 16 (MUC16) in Pancreatic cancer: Expression and Functional Studies.

摘要

Mucins are extensively glycosylated, high molecular weight proteins that protect the epithelial cell layer from a myriad of insults. Apart from normal epithelial cells, cancer cells modulate the expression of mucins to enable disease progression and metastasis. Among cancer associated mucins, Mucin 16 (MUC16) serves as a biomarker for diagnosing and monitoring ovarian cancer patients. MUC16 is also overexpressed in other solid tumors including pancreatic cancer. However, the expression and functional relevance of MUC16 in pancreatic cancer remains largely unknown.;In this dissertation, I investigated the role of MUC16 in pancreatic cancer disease manifestation. My results show that MUC16 expression is elevated during pancreatic cancer progression while it is not detected in the normal pancreas. This instigated me to further probe the functional role of MUC16 in pancreatic cancer. I performed MUC16 knock down studies in pancreatic cancer cell lines, and the knock down cells had decreased growth, tumorigenicity and metastasis.;To further elaborate on the functional role of MUC16, I developed the Muc16-/-; KrasG12D; Pdxl-Cre mouse model, by crossing Muc16 -/- mice with KrasG12D; Pdxl-Cre mice and observed a delay of a period of 10 weeks in the onset of pancreatic cancer as compared to the KrasGl2D; Pdxl-Cre mice. Further we developed the tamoxifen induced KrasG12D; Ptf1a-CreER mouse model, to analyze mucin expression during pancreatic cancer progression that arises from acinar cells. I observed that Mucl and Muc4 expression profile is similar to that observed in the KrasG12D; Pdxl-Cre mouse model. However, Muc16 expression is not detected in this model, indicating that Muc16 expression is induced under the influence of the Pdxl-Cre promoter and not under a Ptf1a-Cre promoter. Hence acinar derived mouse tumor does not express Mucl6. Thus a differential expression profile of mucins might exist in tumors that are derived from different compartments of the pancreas. In conclusion I have experimentally shown that the aberrant up regulation of MUC16 expression in pancreatic cancer contributes towards disease progression using various in vitro and in vivo models.