SRC‐1 functions as a transcriptional coactivator for steroid receptors and various transcriptional factors. Notably, SRC‐1 has been implicated in oncogenic roles in multiple cancers, including breast cancer and prostate cancer. Previous investigations from our laboratory have established the high expression of SRC‐1 in human HCC specimens, where it accelerates HCC progression by enhancing Wnt/beta‐catenin signalling. In this study, we uncover a previously unknown role of SRC‐1 in HCC metastasis. Our findings reveal that SRC‐1 promotes HCC metastasis through the augmentation of MMP‐9 expression. The knockdown of SRC‐1 effectively mitigated HCC cell metastasis both in vitro and in vivo by suppressing MMP‐9 expression. Furthermore, we observed a positive correlation between SRC‐1 mRNA levels and MMP‐9 mRNA levels in limited and larger cohorts of HCC specimens from GEO database. Mechanistically, SRC‐1 operates as a coactivator for NF‐κB and AP‐1, enhancing MMP‐9 promoter activity in HCC cells. Higher levels of SRC‐1 and MMP‐9 expression are associated with worse overall survival in HCC patients. Treatment with Bufalin, known to inhibit SRC‐1 expression, significantly decreased MMP‐9 expression and inhibited HCC metastasis in both in vitro and in vivo settings. Our results demonstrated the pivotal role of SRC‐1 as a critical modulator in HCC metastasis, presenting a potential therapeutic target for HCC intervention.

中文翻译：

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类固醇受体辅激活因子1通过增强MMP-9促进人肝细胞癌侵袭性

SRC-1 充当类固醇受体和各种转录因子的转录共激活子。值得注意的是，SRC-1 与多种癌症的致癌作用有关，包括乳腺癌和前列腺癌。我们实验室之前的研究已经证实 SRC-1 在人类 HCC 标本中高表达，它通过增强 Wnt/β-catenin 信号传导加速 HCC 进展。在这项研究中，我们发现了 SRC-1 在 HCC 转移中的一个先前未知的作用。我们的研究结果表明，SRC-1 通过增强 MMP-9 的表达来促进 HCC 转移。 SRC-1 的敲低通过抑制 MMP-9 的表达，有效地减轻了体外和体内 HCC 细胞的转移。此外，我们在 GEO 数据库中有限和较大的 HCC 样本组中观察到 SRC-1 mRNA 水平与 MMP-9 mRNA 水平之间存在正相关。从机制上讲，SRC-1 作为 NF-κB 和 AP-1 的共激活剂，增强 HCC 细胞中 MMP-9 启动子的活性。 SRC-1 和 MMP-9 表达水平较高与 HCC 患者总生存期较差相关。已知能抑制 SRC-1 表达的 Bufalin 治疗可显着降低 MMP-9 表达，并在体外和体内环境中抑制 HCC 转移。我们的结果证明了 SRC-1 作为 HCC 转移中关键调节剂的关键作用，为 HCC 干预提供了潜在的治疗靶点。