Downregulation of HHLA2 inhibits ovarian cancer progression via the NF-κB signaling pathway and suppresses the expression of CA9

Background: HHLA2 has been recently demonstrated to play multifaceted roles in several types of cancers. However, its underlying mechanism in the progression of human ovarian cancer (OC) remains largely unexplored. In the present study, we aimed to determine whether downregulation of HHLA2 inhibited malignant phenotypes of human OC cells and explore its specific mechanism. Methods: In this study, lentivirus was used to establish individual stable cell lines. In vitro tumorigenesis assays, including cell proliferation, invasion, and wound healing assays were performed to evaluate the biological functions of the target genes in ovarian carcinoma cells. Dual-Luciferase assay was performed to identify the CA9 promoter activity. Animal studies were performed to analyze the effect of HHLA2/CA9 on ovarian cancer progression. Results: Downregulation of HHLA2 significantly suppressed the viability, invasion, and migration of OC cells. Downregulation of HHLA2 in OC cells reduced the expression of CA9 and increased the expressions of p-IKKβ and p-RelA. Conversely, the viability, invasion, and migration of HHLA2-depleted OC cells were increased when CA9 was upregulated. In vivo, we found that downregulation of HHLA2 significantly inhibited tumor growth, which was reversed by CA9 overexpression. In addition, downregulation of HHLA2 inhibited the OC progression via activating the NF-κB signaling pathway and decreasing the expression of CA9. Conclusion: Our data suggested a link between HHLA2 and NF-κB axis in the pathogenesis of OC, and these findings might provide valuable insights into the development of novel potential therapeutic targets for OC.