Date of Award

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Surinder K. Batra

Second Advisor

Michael A. Hollingsworth

Third Advisor

Michel Ouellette

Abstract

Mucins are high molecular weight glycoproteins and have critical functions in protecting epithelial cells from a myriad of cellular stress. However, mucins are expressed aberrantly under cancer conditions that allow tumors to progress and metastasize. Among many mucins, Mucin 4 (MUC4) serves as one of the top-differentially expressed proteins in pancreatic cancer (PC), however, the precise mechanism responsible for its aberrant expression is still not clear. The evolving view of cancer as an energetic and growing ecosystem underlines an intricate interplay between cancer and its microenvironment. In spite of being recognized as one of the most critical oncogenic proteins in PC, MUC4 regulation in terms of micro-environmental stress has not been determined. In my dissertation research, I have investigated the role of PC microenvironment in the regulation of MUC4. From my studies, I have demonstrated that MUC4 stability is significantly reduced due to hypoxia-mediated induction of reactive oxygen species (ROS), which promotes autophagy by inhibiting pAkt/mTORC1 pathway. Hypoxia-mediated degradation of MUC4 provides necessary metabolites to ensure the survival of highly stressed PC cells.

The longstanding model of cancer development involves that presence of cytokines can trigger chronic inflammation and impact tumor development, including PC. In addition to cytokines, bile acids (BA) facilitated chronic inflammation has shown to induce intestinal metaplasia, but their role in PC is still elusive. Elevated levels of BA (p

In addition to the regulation, I have pinpointed the novel functional roles of MUC4 in determining the fate of receptor tyrosine kinases (RTKs) in PC. Multiple studies have associated MUC4 overexpression with increased stability of RTKs for sustained proliferation; however, no studies have so far highlighted the implicated mechanism. I have demonstrated that the presence of MUC4 leads to increased internalization and recycling of EGFR and HER2 to the plasma membrane compared to MUC4 silenced PC cells. Mechanistically, the impact of MUC4 on RTKs trafficking is associated with its ability to regulate the activity of RAB5A, which is known to catalyze the rate-limiting step in receptor internalization. Lastly, I have detected the presence of MUC4 in pancreatic cancer associated stellate cells (PaSC). This was an unexpected finding given that MUC4 is normally expressed in the epithelial cells. These results indicate towards the involvement of MUC4 expression in determining the activation status of PaSC and provide us an additional strong rationale to therapeutically target MUC4.

Altogether, in my dissertation research, I have elucidated the novel regulatory mechanisms and functions of MUC4 in PC condition.

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