Unveiling the Role of Nuclear Export Protein 1 (XPO1)-microRNA Axis within Gastric Cancer

Gastric cancer is a deadly disease that disproportionately impacts the African American community with decreased survival rates. It is largely unknown why this occurs but various proteins controlled by nuclear export protein 1 (XPO1/CRM1) are perturbed in African American gastric cancers at a higher rate. Although this is the case, there have been no conclusive studies identifying the connection between aberrant XPO1 activity and disparities. As part of our proposed Aim 1, we have obtained over 200 normal and gastric cancer patient tissues of African American and Caucasian American ethnicity and found a significant increase in XPO1 expression within the African American cohort (94% vs. 79%) but future investigation is underway to correlate XPO1 expression to overall survival in a retrospective analysis. We were one of the first groups to find XPO1 overexpression in gastric cancer compared to normal tissue and identify a molecular rationale that targeting this protein, with the small molecule inhibitor Selinexor (KPT-330), which is effective in targeting this disease. We have found that XPO1 inhibition targets the elicit perturbation of gastric cancer specific microRNAs that are responsible for disease progression, such as miR-7974 and miR-129-1-3p, and others which can be captured within the tumor and the serum. We have confirmed that up regulation of miR-7974 and downregulation of miR-129-1-3p leads to an increase in gastric cancer growth through targeting specific cancer related pathways including RASGEF1A (cell growth), TIMP2 (metastasis), DRAM1 (autophagy) and CCNG2 (cell cycle). This needs to be further confirmed in distinct gastric cancer cell line models.