Loss of the predicted cell adhesion molecule MPZL3 promotes EMT and chemoresistance in ovarian cancer
Myelin protein zero-like 3 (MPZL3) is an Immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, where the MPZL3 gene resides, is frequently observed in cancer. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, where both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. While high and low MPZL3 expressing populations are similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely display decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knock-down leads to an increase in EMT gene expression in OVCAR4 and OVCA433 cell lines, a transcript signature that is associated with poor patient outcomes. MPZL3 promotes homotypic cancer cell adhesion in some cell lines, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. Conversely, MPZL3 loss abrogates cell cycle progression and proliferation. This was associated with increased resistance to cisplatin and olaparib and reduced DNA damage and apoptosis in response to these agents in OVCAR4 cells. Enhanced cisplatin resistance was further validated in vivo. These data demonstrate for the first time that loss of the predicted adhesion molecule MPZL3 results in EMT and decreased proliferation in ovarian cancer. Our study suggests that decreased MPZL3 expression is a phenotype of ovarian cancer tumor progression and metastasis and may contribute to treatment failure in advanced-stage patients. Overall design: To investigate the role of MPZL3 in ovarian cancer cell line OVCA433, MPZL3 expression was knocked down using two indepdent shRNA hairpins (shRNA#1 - TRCN0000137304, shRNA#3 - TRCN0000137252) and RNA sequencing carried out.