Date of Award

2014

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Pier Paolo Claudio

Second Advisor

Richard Niles

Third Advisor

W. Elaine Hardman

Fourth Advisor

Jagan Valluri

Fifth Advisor

Piyali Dasgupta

Abstract

A commonality among cancer types is the high frequency of mutations that inhibit or alter signaling of the p53 and pRb (Retinoblastoma) tumor suppressors. These genes regulate processes vital for cancer suppression such as apoptosis, senescence, and cell cycle arrest among others. Loss of both p53 and pRb promotes processes that support cancer progression and is associated with decreased patient survival and increased rates of tumor reoccurrence. Although data points to the ability of p53 and pRb to collaborate and to inhibit tumorigenesis, it remains unclear how p53 and pRb cooperate toward this task. Using RNA expression profiling, 179 p53 and pRb cross-talk candidates were identified in normal lung fibroblasts (WI38) cells exogenously coexpressing p53 and pRb. Regulator of G protein signaling 16 (RGS16) was among the p53 and pRb cross-talk candidates and reports suggest it inhibits the activation of several oncogenic pathways associated with proliferation, migration, and invasion of cancer cells.

RGS16 is downregulated in pancreatic cancer patients with metastases compared to patients without metastasized pancreatic cancer. The role of RGS16 in cancer cell metastasis is unknown; therefore I tested the hypothesis that RGS16 inhibits pancreatic cancer cell migration and invasion in vitro. Expression of RGS16 was decreased in the pancreatic cancer cell lines tested compared to control. Expression of RGS16 inhibited fetal bovine serum (FBS) and epidermal growth factor (EGF) induced migration of the BxPC-3 and AsPC-1 but not PANC-1 pancreatic cancer cells. It also inhibited EGF induced invasion of BxPC-3 and AsPC-1 cells with no impact on cell viability. Although RGS16 inhibited cell migration and invasion of BxPC-3 and AsPC-1 cells, there was no change in F-actin polymerization or the amounts of p-AKT, pERK and the epithelial mesenchymal transition (EMT) marker vimentin proteins, but there was a slight increase in E-cadherin protein expression in BxPC-3 cells. Our data suggests the inhibitory effect of RGS16 on EGF induced pancreatic cancer cell migration is independent of the PI3K and MAPK pathways. To our knowledge, for the first time, we performed analyses to identify p53 and pRb cross-talk candidates and demonstrated a role for RGS16 in suppressing EGF and FBS induced pancreatic cancer migration and invasion.

Subject(s)

Cancer cells - Growth.

Cancer cells - Research.

Pancreas -- Cysts- Research.

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