LncRNA-SARCC调控雄激素受体影响肾细胞癌侵袭和转移的作用与机制研究

The metastasis prognosis of renal cell carcinoma (RCC) is poor. The roles of LncRNAs are largely unknown. It has been reported that LncRNA-SARCC could affect the proliferation of RCC under hypoxic condition, but it is still unclear whether it refers to the metastasis of RCC. In the previous study, we found that the expression of LncRNA-SARCC in RCC tissue was lower and was positively correlated with the prognosis of patients. The inhibition of LncRNA-SARCC promoted the migration and invasion of RCC cell lines. In addition, we presented that LncRNA-SARCC binding to androgen receptor (AR) mediated AR through ubiquitination. Therefore, we propose the hypothesis that LncRNA-SARCC modulates the invasion and metastasis of RCC via regulating AR. We will identify and validate the levels of LncRNA-SARCC in RCC clinical samples and its relationship with prognosis. We will overexpress LncRNA-SARCC to explore its biological functions in RCC in vitro. Meanwhile, we will demonstrate the interaction of LncRNA-SARCC and AR and the effect of the miR-143-3p signaling pathway. In this study, we will impart the new mechanism of RCC metastasis from the perspective of LncRNAs, and provide a new theoretical foundation for the treatment of RCC.

肾癌转移预后较差，长链非编码RNA（LncRNA）在肾癌转移中的作用尚不明确。申请者前期报道在缺氧条件下LncRNA-SARCC能影响肾癌细胞的增殖，但它是否参与肾癌转移仍不清楚。本项目前期研究发现LncRNA-SARCC在肾癌组织中低表达并和患者预后呈正相关。沉默该LncRNA促进肾癌细胞的迁移和侵袭。此外我们发现LncRNA-SARCC能结合并泛素化调控雄激素受体（Androgen Receptor, AR）。因此我们认为：LncRNA-SARCC通过调控AR影响肾细胞癌侵袭和转移。为了验证假说，我们将进一步明确LncRNA-SARCC在临床中的表达及预后；建立该LncRNA过表达细胞模型，探讨其在肾癌中的生物学功能；进一步论证LncRNA-SARCC与AR相互作用及对下游miR-143-3p信号通路的调控。本课题将从LncRNA的角度揭示肾癌转移的新机制，为肾癌治疗提供新的理论基础。

肾癌转移预后较差，lncRNA在肾癌转移中的作用尚不明确。在本项课题中，申请人研究发现和正常肾组织相比，LncRNA-SARCC在肾癌组织中表达量较低。LncRNA-SARCC表达高的肾癌患者5年生存率相对较好，LncRNA-SARCC表达低的肾癌患者5年生存率相对较差。沉默LncRNA-SARCC促进肾癌细胞的迁移和侵袭，过表达LncRNA-SARCC可以抑制肾癌细胞的迁移和侵袭，分子机制层面上，LncRNA-SARCC结合AR蛋白并通过泛素化方式降解AR蛋白，形成LncRNA-SARCC/AR转录复合体导致转录抑制下游miR-143-3p表达，进而抑制下游信号AKT、MMP-13、K-RAS、P-ERK等基因表达。此外，亚硫酸氢钠测序分析证实了，和癌旁肾组织相比，LncRNA-SARCC启动子区在肾癌组织中高度甲基化，从而抑制了其在肾癌中的表达。值得注意的是，多靶点受体酪氨酸激酶抑制剂舒尼替尼能明显增加LncRNA-SARCC表达，从而减少肾癌细胞对舒尼替尼的抗药性。因此，申请人的研究成果从lncRNA角度出发为肾癌转移的机制和靶向治疗提供了一项潜在的治疗策略。