Hydnocarpin D‐induced microRNA‐145‐5p down‐regulates SERPINE1 and suppresses metastasis in ovarian cancer

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BACKGROUND AND PURPOSE: Hydnocarpin D (HD) is a flavonolignan compound isolated from Hydnocarpus wightiana. This study was to investigate the effect of HD on ovarian cancer mediated by the regulation of SERPINE1. EXPERIMENTAL APPROACH: Cytotoxicity was assessed by the MTT assay. Cell migration and invasion were examined using wound healing and Boyden chamber assays. An orthotopic xenograft model was constructed to determine the inhibitory effect of HD on ovarian cancer in vivo. Differential gene expression was screened by RNA sequencing. A 3'-UTR luciferase assay was performed to confirm the regulatory effect of microRNA-145-5p on SERPINE1. Small interfering RNA and microRNA mimics/inhibitors were introduced to elucidate the mechanism. KEY RESULTS: HD inhibited the migration and invasion of SKOV3 and OVCAR4 cells without showing cytotoxic effects. HD inhibited the growth and metastasis of ovarian cancer in vivo. RNA-sequencing analysis suggested that HD suppressed metastasis by inhibiting SERPINE1 expression. Free uPA, which is not bound to PAI-1 (SERPINE1), was up-regulated, whereas vitronectin, integrin αV and phosphorylated FAK, the downstream metastasis-related signalling factors for PAI-1, were down-regulated after treatment with HD. SERPINE1 inhibition attenuated the effect of HD on reducing cell migration and rhPAI-1 enhanced the effect of HD. We identified microRNA-145-5p as the post-transcriptional repressor of SERPINE1. MicroRNA-145-5p was up-regulated by HD, and its overexpression enhanced the inhibition of PAI-1 expression and migration by HD, whereas its inhibition had the opposite effect. CONCLUSION AND IMPLICATIONS: We showed that HD inhibits metastasis in ovarian cancer by up-regulating microRNA-145-5p, which targets SERPINE1, inhibiting vitronectin/integrin/FAK signalling.

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