Access Type

Dissertation/Thesis

Date of Award

January 2019

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmacology

First Advisor

Karin List

Second Advisor

Sokol V. Todi

Abstract

Colorectal cancer (CRC) is one of the most common and deadly cancers in both men and women in the United States. Extracellular proteolysis is often dysregulated in cancer including (CRC), resulting in degradation of extracellular matrix, as well as cleavage, processing, or shedding of cell adhesion molecules, growth factors, and cytokines. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression; however, many family members have not yet been characterized in malignancy. We identified TMPRSS13 transcript to be upregulated in CRC compared to normal colon. This increase was confirmed at the protein level by immunohistochemical analysis of CRC tumor tissue arrays. Mechanistic studies revealed increased apoptosis an impaired invasive potential following TMPRSS13 silencing in human CRC cells. Importantly, TMPRSS13 gain-of-function promoted resistance to the apoptosis-inducing agents paclitaxel and HA14-1 Reversely, TMPRSS13 loss-of-function caused increased sensitivity of CRC cells to drug-induced apoptosis. Use of a TMPRSS13-deficient mouse line in the azoxymethane/dextran sulfate sodium (DSS) model of CRC revealed increased sensitivity to DSS treatment. This sensitivity manifested as increased colitis and severe weight loss indicative of a defect in intestinal barrier function. TMPRSS13-deficient mice also exhibited greater tumor burden compared to wild-type mice, likely as a result of increased severity of colitis. Together these findings demonstrate a critical role for TMPRSS13 in pro-oncogenic processes as well as intestinal homeostasis and identify TMPRSS13 as potential novel target for CRC cancer therapy.

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