LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor (AR)/miRNA-143-3p signals
LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor (AR)/miRNA-143-3p signals
复制标题
LncRNA-SARCC 通过改变雄激素受体 (AR)/miRNA-143-3p 信号抑制肾细胞癌 (RCC) 进展
DOI：
10.1038/cdd.2017.74
复制
发表时间：
2017-09-01
影响因子：
12.4
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
--
作者：
Zhai, Wei;Sun, Yin;Chang, Chawnshang
虽然雄激素受体（AR）可能促进肾细胞癌（RCC）的发生和发展，但其分子机制仍不清楚。在这里，我们发现了新的LncRNA-SARCC，它在RCC中被抑制并与更好的预后相关。利用多个RCC细胞和体内小鼠模型进行的临床前研究表明，LncRNA-SARCC在体外和体内均能抑制RCC细胞的侵袭、迁移和增殖。在机制上，LncRNA-SARCC结合AR蛋白并使其不稳定，同时抑制AR功能，这导致转录去抑制miR-143- 3 p表达，从而抑制其下游信号包括AKT、MMP-13、K-RAS和P-ERK。此外，亚硫酸氢盐测序分析证实，与配对的非癌肾组织相比，LncRNA-SARCC启动子在肾癌组织中高度甲基化。值得注意的是，用舒尼替尼（多靶向受体酪氨酸激酶抑制剂）治疗增加了LncRNA-SARCC的表达，从而降低了RCC细胞对舒尼替尼的耐药性。因此，我们的研究为靶向这种新发现的LncRNA-SARCC及其通路提供了路线图，这扩大了RCC治疗的潜在治疗策略。
While the androgen receptor (AR) might promote renal cell carcinoma (RCC) initiation and progression, the molecular mechanisms involved remain largely unclear. Here, we discovered the novel LncRNA-SARCC, which was suppressed and associated with better prognosis in RCC. Preclinical studies using multiple RCC cells and in vivo mouse model indicated that LncRNA-SARCC could attenuate RCC cell invasion, migration and proliferation in vitro and in vivo. Mechanistically, LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR-143-3p expression, thus inhibition of its downstream signals including AKT, MMP-13, K-RAS and P-ERK. In addition, bisulfite sequencing analysis substantiated that LncRNA-SARCC promoter was highly methylated in renal cancer tissues compared with paired non-cancerous renal tissues. Notably, treating with Sunitinib, the multi-targeted receptor tyrosine kinase inhibitor, increased the expression of LncRNA-SARCC, which decreased RCC cells resistance to Sunitinib. Thus, our study presented a road map for targeting this newly identified LncRNA-SARCC and its pathway, which expands potential therapeutic strategies for RCC treatment.