Abstract 2881: Snail-mediated regulation of MMP1 expression in the context of ovarian cancer invasiveness

Abstract

Abstract Ovarian cancer ranks fifth among the causes of cancer death in US women. Despite initial positive response to cytoreductive surgery and chemotherapy treatments with platinum-based therapies, over 80% of patients with high-grade serous ovarian cancer (HGSOC), the most common type of ovarian cancer, exhibit relapse. Most recurrent cases of HGSOC are resistant to chemotherapy, and cells are highly invasive. Therefore, further studies are required to understand the mechanisms of invasiveness and chemoresistance in relapse patients. In HGSOC, invasiveness can result when epithelial cancer cells undergo epithelial-mesenchymal transition (EMT). The transcription factor SNAI1 (Snail) initiates the EMT process and increased Snail expression can result in enhancement of metastatic potential, acquisition of stem cell-like characteristics, and resistance to chemotherapeutic drugs. However, the mechanism of activation of invasiveness in ovarian cancer by Snail has not been defined. In OVCAR8, a HGSOC cell line, comparison of shSnail knockdown to control through RNA-sequencing revealed that Snail expression is directly correlated to matrix metalloprotease 1 (MMP1) expression. MMP1 is an extracellular matrix remodeler known to digest interstitial collagens. High MMP1 expression has been linked to increased cancer invasion, metastasis, angiogenesis, and apoptosis. Furthermore, in breast cancer, MMP1 has been reported to be a downstream target of Slug, another major EMT transcription factor. Some evidence for Snail activation of MMPs in liver cancer has been presented, but a direct relationship has not been established. Therefore, we hypothesize that overexpression of Snail in ovarian cancer cells results in MMP1 upregulation, leading to increased invasion. RT-qPCR was performed to analyze relative mRNA expression levels of Snail and MMP1 in eight cell lines. We found that Snail and MMP1 levels were higher in the more mesenchymal-like cell lines, some of which are known to be more invasive. Additionally, Snail overexpression led to a significant corresponding increase in MMP1 mRNA expression and resistance to cisplatin. Chromatin immunoprecipitation (ChIP) experiments demonstrate Snail binding to the MMP1 promoter. Thus, our preliminary findings have shown strong evidence of a Snail-mediated regulation of MMP1 expression in the context of HGSOC invasiveness. Citation Format: Tise Suzuki, Casey Curow, Hanmin Wang, Asis Martinez, Nozomi Hojo, Juli Unternaehrer. Snail-mediated regulation of MMP1 expression in the context of ovarian cancer invasiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2881.