Abstract
Abstract Introduction: Long non-coding RNAs (lncRNAs) are important regulators of gene expression and are involved in cancer progression and metastasis. Although studies have shown that aberrant expression of lncRNAs mediates disease progression in ovarian cancer (OC), the role of lncRNA ADAMTS9-AS2 has not been well studied. Objective: To determine the role of ADAMTS9-AS2 on OC pathogenesis. Methods: We examined ADAMTS9-AS2 expression in human OC cells and tumor tissues using in situ hybridization (ISH). ADAMTS9-AS2 was overexpressed in A2780cp20 and IGROV1cp20 cells and evaluated its effects on cell proliferation, viability and apoptosis. To evaluate the role of ADAMTS9-AS2 in tumor suppression, nude mice were injected with ADAMTS9-AS2 over expressing cells. Reverse phase protein array (RPPA) was performed to identify the downstream regulators. Luciferase reporter assay was performed to confirm the interaction of targeted protein with ADAMTS9-AS2. In addition, epigenetic regulation of ADAMTS9-AS2 was studied using 5-Azacytidine. Results: A2780cp20 and IGROV1cp20 cells expressed lower amounts of ADAMTS9-AS2, while SKOV3 and PEO4 cells showed higher expression levels. ISH analysis showed dense nuclear staining of ADAMTS9-AS2 in normal fallopian tube sections, whereas OC sections showed reduced expression. Kaplan-Meier survival analysis showed that patients with high expression of ADAMTS9-AS2 had significantly better overall survival (p=0.0079) and progression-free survival (p=0.00018) than those with low ADAMTS9-AS2 expression. Overexpression of ADAMTS9-AS2 in A2780cp20 cells resulted in decreased proliferation (p<0.01) and increased apoptosis (p<0.001). ADAMTS9-AS2 overexpressing A2780cp20 and IGROV1cp20 tumor bearing mice showed significant reduction in tumor growth (p=0.002; A2780cp20, p=0.01; IGROV1cp20) when compared to control A2780cp20 and IGROV1 tumor bearing mice. RPPA analysis showed that ANNEXIN A1 was the most upregulated protein upon ADAMTS9-AS2 overexpression. We confirmed that ANNEXIN A1 expression is regulated by ADAMTS9-AS2 by silencing ADAMTS9-AS2. Further, luciferase reporter assay results confirmed the interaction between ADAMTS9-AS2 and ANNEXIN A1 promoter and silencing ADAMTS9-AS2 with siRNA abolished this effect. Consistently with our previous in vitro findings, we observed a significant increase of ANNEXIN A1 expression in the ADAMTS9-AS2 overexpressing mice, compared with the A2780cp20 control. Further, azacytidine treated A2780cp20 cells showed an increase in ADAMTS9-AS2 expression. Conclusion: ADAMTS9-AS2 acts as a tumor suppressor, by enhancing the expression of ANNEXIN A1, and thereby regulating tumor growth. Thus, ADAMTS9-AS2-ANNEXIN A1 axis may represent a novel therapeutic target in OC. Citation Format: Emine Bayraktar, Guy Katz, Dahai Jiang, Cristian Rodriguez-Aguayo, Lingegowda S. Mangala, Santosh K. Dasari, Elaine Stur, Cristina Ivan, Gabriel Lopez-Berestein, Anil K. Sood. Elucidating the role of ADAMTS9AS2 lncRNA in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1550.
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