Access Type

Open Access Dissertation

Date of Award

January 2022

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Asfar S. Azmi

Abstract

Gastric cancer is a leading cause of cancer related deaths worldwide. Throughout the world, there is around one million new diagnosed cases per year and only an approximate 25% survival rate. This disease is highly heterogeneous, chemotherapy resistant and deadly. Currently there is no gold standard for care but rather it is physician’s choice. Various chemotherapeutic agents can be used including microtubule inhibitors, DNA damaging agents and anti-metabolite compounds. We have found that nuclear export protein 1 (XPO1) is overexpressed in gastric cancer patients and cell lines compared to normal gastric tissues leading to an aggressive cancerous phenotype that is perpetuated by this genetic aberration. The result of XPO1 overexpression leads to enhanced growth signaling pathways, such as KRAS activation. We have found that the African American gastric cancer cohort has increased expression of XPO1 compared to the white gastric cancer cohort and is a possible explanation for cancer related disparities found within this disease. We have further found that inhibition of XPO1, with siRNA, results in suppression of gastric cancer growth and viability. Using selective inhibitors of nuclear export (selinexor, eltanexor), that have recently achieved FDA approval in other malignancies; we have found these compounds are effective in reducing gastric cancer growth both in vitro and in vivo. We have found inhibition of XPO1 is also an effective strategy to overcome resistance to commonly used chemotherapeutics caused by microtubule inhibitors (taxols), DNA damaging agents (platinum’s) and anti-metabolites (5-fluorouracil) both in vitro and in vivo. Last, we have found that overexpression of XPO1 leads to the differential expression of cancer driving small noncoding RNAs, relevant to gastric cancer, which is involved with perpetuating cancer growth and viability and XPO1 suppression with SINEs alters the expression of these microRNAs. The interaction between XPO1 and small noncoding RNAs is an alternative mechanism of transport that is normally carried out by nuclear export protein 5 (XPO1). Within gastric cancer, we have focused on two particular microRNAs for further evaluation: miR-7974 and miR-129-1-3p. We have found these microRNAs are differentially expressed in gastric cancer cell lines compared to normal tissues. These findings correlates with literature studies of these microRNAs in other disease models. We have also uncovered that aberrant expression of these microRNAs leads to selinexor resistance in two gastric cancer cell lines. Future biomarker studies are needed to explore the therapeutic potential of these small-noncoding RNAs in gastric cancer.

Download

Included in

Biology Commons

Share

COinS