Graduation Date

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Dr. Surinder K. Batra

Abstract

Secretory mucin MUC5AC is an extensively glycosylated high molecular weight protein that forms a polymeric gel layer over the epithelial layers under physiological conditions, to protect these surfaces from myriad of insults. MUC5AC is known to be implicated in various malignancies including pancreatic cancer and colorectal cancer. MUC5AC is overexpressed in pancreatic cancer compared to no expression in normal pancreas. However, its functional implications and associated mechanistic basis in pancreatic cancer remains obscure. Therefore, we investigated the role of MUC5AC in onset and progression of pancreatic cancer. Our study showed that MUC5AC expression is elevated during pancreatic cancer progression while it was not detected in the normal pancreas. To elucidate the functional role of MUC5AC in pancreatic cancer, we performed MUC5AC knockdown studies in pancreatic cancer cell lines (FG/COLO357, SW1990). Knockdown of MUC5AC decreased pancreatic cancer cell viability, tumorigenicity, metastasis, angiogenesis, and increased sensitivity to Gemcitabine. We observed that MUC5AC might impact pancreatic cancer cell growth and metastasis by its interactions with E-Cadherin and β-Catenin. To further elaborate the functional role of MUC5AC, we developed the KrasG12D; Pdx1-Cre; Muc5ac-/- mouse model by crossing Muc5ac-/- mice with pancreatic cancer mice model- KrasG12D; Pdx1-Cre mice. A delay in the onset as well as the progression of pancreatic cancer was observed in KrasG12D; Pdx1-Cre; Muc5ac-/- mice as compared to the control KrasG12D; Pdx1-Cre mice.

Further, MUC5AC is not expressed in the normal colon, but it is de novo expressed during early stages and further increases during progression to advanced stages of colorectal malignancy. Despite association of increased MUC5AC levels with conventional and serrated neoplasia pathway of colorectal carcinogenesis, the diagnostic utility of MUC5AC for predicting future colorectal malignancy remained unexploited. Hence, we also explored the diagnostic utility of MUC5AC in conjunction with other differentially expressed mucins and mucin-associated glycans to predict colorectal malignancy. The study findings revealed an improved efficacy of combined MUC2, MUC5AC, and MUC17 expression for differentiating premalignant and/or malignant lesions from benign polyps. Furthermore, we addressed the problem of current non-availability of specific and sensitive markers to discriminate benign hyperplastic polyps from sessile serrated and tubular adenomas. We identified a combinatorial panel of mucins and glycoepitope based molecular markers (CA 19-9/MUC17/MUC5AC) that could discriminate sessile serrated adenoma/polyps and tubular adenomas from benign hyperplastic polyps with high sensitivity and specificity.

Overall, our studies demonstrate that MUC5AC plays a key role in onset and progression of pancreatic cancer. Further, our findings indicate that in conjunction with other differentially expressed mucins and associated glycans, MUC5AC may significantly improve the early stage diagnosis of colorectal cancer.

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