Abstract 1579: Matrix metalloproteinase 1: Oncogene or tumor suppressor in ovarian cancer

Abstract

Abstract Purpose: The high risk of tumor recurrence and subsequent development of chemotherapy resistance plays a major role in the high mortality rate for high grade serous ovarian cancer (OC) patients. To investigate genes contributing to OC progression, we analyzed gene expression arrays for 21 primary versus 21 recurrent OCs. Matrix Metalloproteinase-1 (MMP-1), an extra cellular matrix (ECM) factor, showed significantly increased expression in recurrent OC. MMPs play important roles in the tumor microenvironment (TME) and are associated with metastasis in certain cancers. However, regulation of MMP-1 expression and its role in ovarian cancer are not well understood. In this study, we examined the role of MMP-1 in proliferation, migration/invasion, and chemosensitivity as well as response to environmental conditions in OC cell lines. Experimental Procedures: Gene expression data was generated for 21 primary/recurrent OCs using the Affymetrix U133A 2.0 array and compared using t tests. shRNA was used for stable knockdown of MMP-1 in CAOV2 OC cells and WI38 fibroblasts, the latter of which were used to generate conditioned media with low MMP-1 (CMMMP-1 low). Non-silencing shRNA was used as control for off-target effects (CMMMP-1 Ctl). Cell migration was assessed using wound healing assays. Cell proliferation and response to carboplatin and paclitaxel (PTX) were measured using cell viability assays. MMP-1 promoter methylation was evaluated using pyrosequencing of bisulfite modified DNA from cells treated with decitabine vs vehicle. MMP-1 expression was also examined in cells grown in media with pH 6.2, 7.2, and 8.2, in media depleted of methionine and under hypoxic conditions. Results: Average MMP-1 expression was roughly 2.5-fold higher in recurrent vs primary OC (p=0.045). Both CAOV2 cells with MMP-1 knockdown and CAOV2 cells cultured in CMMMP-1low showed increased proliferation, and enhanced resistance to carboplatin and PTX (p=0.03 for Carboplatin treatment, p=0.04 for PTX treatment). MMP-1 expression increased in OC cells when DNA methylation was inhibited by decitabine treatment which was shown with pyrosequencing analysis covers the MMP-1 promotor region. In addition, MMP-1 expression increased in more acidic media as well as in the absence of methionine and under hypoxic conditions. Conclusions: In contrast to reports of the more aggressive phenotype associated with MMP-1 in other types of cancers, CAOV2 OC cells with higher levels of MMP-1 in the media have a less aggressive phenotype, indicating that the effects of MMP-1 are context-dependent. The ability of cells to alter MMP-1 expression with varying culture conditions suggests that MMP-1 may have an important role in modulating OC cell behavior in response to the microenvironment during disease progression. Citation Format: Zhiqing Huang, Cassie Hobbs, Olivia Neely, Derek Y. Yao, Junhee Shin, Carole Grenier, Susan K. Murphy. Matrix metalloproteinase 1: Oncogene or tumor suppressor in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1579.