Date of Award

8-1-2015

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

CAO, DELIANG

Abstract

AN ABSTRACT OF THE DISSERTATION OF Chenfei Huang, for the Doctor of Philosophy degree in Molecular Cancer Biology, presented on June 24th, 2015, at Southern Illinois University Carbondale. TITLE: AKR1B10 PROMOTES BREAST CANCER METASTASIS THROUGH INTEGRIN α5/δ-CATENIN-RAC1 SIGNALING PATHWAY MAJOR PROFESSOR: Dr. Deliang Cao Aldo-keto reductase 1B10 (AKR1B10) is not expressed in normal breasts, but upregulated in primary and metastatic breast cancers, being a negative prognostic marker. This study characterized the molecular mechanisms of action of AKR1B10. Ectopic expression in breast cancer cells MCF-7 and MDA-MB-231 or siRNA-mediated silencing in BT-20 cell of AKR1B10 affected cell adhesion, migration and invasion, as well as metastasis to the lung in mouse models, through regulation of the expression of cell adhesion molecules (CAMs), e.g., integrin α5, δ-catenin and fibronectin. Silencing of integrin α5 and δ-catenin synergistically eradicated the cell adhesion and migration enhanced by AKR1B10. In human primary and lymph node metastatic breast cancers, the integrin α5 and δ-catenin expression was increased and their expression was correlated with AKR1B10 levels. In MCF-7 and BT-20 cells, AKR1B10 activated the integrin α5-mediated focal adhesion kinase (FAK) signaling pathway which, together with δ-catenin, stimulated Rac1-mediated cell migration and movement. Furthermore, we found that in these cancer cells, AKR1B10 activated protein kinase C (PKC) which in turn activated the c-Raf-1/MEK/ERK signaling cascade and triggered integrin α5 and δ-catenin expression. Together our data suggest that AKR1B10 promotes breast cancer metastasis through activation of PKC/ERK signaling pathway and upregulation of ii integrin α5 and δ-catenin. Rac1 acts as a common downstream effector of both integrin α5 and δ-catenin in breast cancer cell movement.

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