Date of Award

Spring 5-6-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Dr. Jing Wang

Abstract

Early in colorectal cancer development, there is loss of tumor suppressor pathways and gain of oncogenic pathways. TGFBeta signaling acts as a tumor suppressor pathway early in cancer development by regulating transcription factors that are responsible for cellular growth and apoptosis. Unfortunately, some aspect of the TGFBeta signaling pathway is lost in approximately 30-40% of colorectal cancer patients. Another pathway that is deregulated in 30% of human colon cancer is the oncogenic IGF-1R pathway. The dysregulation of these pathways leads to colorectal cancer progression.

The TGFBeta signaling pathway activates the receptor-regulated Smads (Smad2/3) that translocate into the nucleus and regulate various target genes. Previous studies have shown that Smad2 and Smad3 can play different roles in the progression of cancer. In PDAC cells, the knock down of Smad3 led to increased proliferation, while the knock down of Smad2 decreased cellular migration. Studies from our lab have shown repression of vascular endothelial growth factor A (VEGFA) expression was TGFBeta/Smad3 dependent but not Smad2. Another lab looked at the different types of proteins that interacted with Smad2 and Smad3. Insulin Receptor Substrate (IRS)-1 was found to associate with Smad3.

IRS-1 is an adaptor protein in the IGF-1R signaling pathway. When IGF-1R becomes auto phosphorylated, then IRS-1, or IRS-2, can bind and create docking sites for downstream signaling pathways involved in promoting tumorigenesis. We found that with the loss of TGFBeta signaling there was increased expression and phosphorylation of IRS-1 that was associated with increased proliferation and decreased cell death. We concluded that IRS-1 was being regulated in a TGFBeta/Smad3-dependent manner. Upon knocking down Smad2, we observed decreased expression and phosphorylation of IGF-1R and the downstream markers, along with decreased proliferation and increased cell death. We demonstrated for the first time Smad2 and Smad3 have antagonist roles in the progression of colorectal cancer.

The significance of this dissertation work is the identification of the novel cross talk between TGFBeta and IGF-1R signaling at the level of Smad2 and Smad3 regulation. These results give insight into new potential therapeutic targets and a better understanding of how the TGFBeta and IGF-1R signaling pathways are working during the progression of colorectal cancer.

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