Toward understanding the roles of matrix metallopeptidase 1 in ovarian cancer

Abstract

Ovarian Cancer (OC) is the leading cause of gynecologic cancer-related deaths worldwide. The leading risk factors for OC-related death are OC recurrence and the development of chemotherapy resistance. Investigation into molecular differences that distinguish primary from recurrent disease and the role of the tumor microenvironment (TME) in OC progression may help identify therapeutic targets. Gene expression microarray data comparisons between 21 primary and 21 recurrent OC specimens (16 matched pairs) showed significantly increased expression of Matrix Metallopeptidase 1 (MMP1) in the recurrent specimens (p = 0.03). We, therefore, investigated MMP1 expression regulation and how endogenous and exogenous MMP1 expression influences OC cell proliferation, migration/invasion and chemosensitivity. Both endogenous MMP1 knockdown and low levels of exogenous MMP1 increased cell proliferation of the OC cell line, CAOV2 (p < 0.01 and p < 0.001, respectively). Furthermore, CAOV2 cells cultured with low exogenous MMP1 exhibited increased invasion (p = 0.04 and p = 0.002, respectively, for two shRNA-conditioned mediums, shMMP1-1 or shMMP1-2) and faster migration by wound healing assay relative to controls without MMP1 knockdown. CAOV2 MMP1 knockdown cells were also more resistant than controls to carboplatin (p = 0.04) and paclitaxel (p = 0.017). To explore the functions of cancer environmental MMP1 in different cancer cells, 3 OC cell lines (CAOV2, HEYA8 and SKOV3) were tested for their proliferation when cultured under a low MMP1 conditioned medium. Interestingly, while the proliferation was increased in CAOV2 and HEYA8 cells, it was reduced when SKOV3 OC cells were cultured with low exogenous MMP1 (CAOV2: * p = 0.01, HEYA8: **** p = 0.0004, SKOV3: ** p = 0.002). These results likely reflect inherent MMP1 expression variability in OC tissues and cell lines that is at least partly dependent on other endogenous parameters of the TME, including pH, metabolic state, and oxygenation, all of which were found to alter levels of endogenous MMP1. Given the ability of MMP1 to promote oncogenic or tumor-suppressive behaviors, further study will be necessary to better understand how MMP1 contributes to promoting or restraining tumor progression in an individualized manner.