Steroid Receptor Coactivator 1 Promotes Human Hepatocellu-lar Carcinoma invasiveness Through Enhancing MMP-9

Abstract Backgroud: SRC-1 works as a transcriptional coactivator for steroid receptors and other transcrip-tional factors. SRC-1 is shown to play oncogenic roles in many cancers, like breast cancer and prostate cancer. Our lab anteriorly accounted that SRC-1 is highly expressed in human HCC spec-imens. SRC-1 accelerates HCC progression via enhancing Wnt/beta-catenin signaling. However, the role of SRC-1 in HCC metastasis is unknown. Methods: RNA inteference was used to knockdown the expression of SRC-1, and the protein level was detected via Western blot assay. Matrigel invasion assay was performed for assessment of HCC cell metastasis. MMP9 expression was detected via Zymography. Luciferase assays were performed to detect MMP-9 promoter activity. Results: In this study, we report that SRC-1 promotes HCC metastasis through enhancing MMP-9 expression. Knockdown of SRC-1 decreased HCC cell metastasis in vitro and in vivo by inhibiting the expression of MMP-9. SRC-1 mRNA level is found to positively correlated with MMP-9 mRNA level in a limited number cohort of HCC specimens and a larger number cohort of HCC specimen from GEO database. SRC-1 functions as a coactiva-tor for NF-κB and AP-1 to regulate MMP-9 promoter activity in HCC cells. Higher SRC-1 and MMP-9 expression correlates with a worse overall survival in HCC patients. Bufalin treatment, which can inhibit SRC-1 expression, can significantly decreased MMP-9 expression and inhibit HCC metastasis both in vitro and in vivo. Conclusion: Our results demonstrated that SRC-1 is a crucial modulator for HCC metastasis and offered a potential target for HCC therapy.