Upregulation of RICTOR gene transcription by the proinflammatory cytokines through NF-κB pathway contributes to the metastasis of renal cell carcinoma
Upregulation of RICTOR gene transcription by the proinflammatory cytokines through NF-κB pathway contributes to the metastasis of renal cell carcinoma
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促炎细胞因子通过 NF-κ B 途径上调 RICTOR 基因转录有助于肾细胞癌的转移
DOI：
10.1007/s13277-015-4296-z
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发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Zhang, Ning
中科院分区：
文献类型：
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作者：
Sun, Bo;Chen, Liwei;Zhang, Ning
转移占肾细胞癌（RCC）患者死亡的50%以上，因此，重要的是研究转移的生物学并鉴定转移相关的生物标志物用于RCC的个体化治疗的风险预后和患者分层。在培养的RCC细胞中，通过短发夹RNA（shRNA）敲低Rictor抑制细胞迁移和侵袭，可能是由于Akt活化受损。用肿瘤坏死因子α（TNF α）或白细胞介素6（IL-6）预处理可增强Rictor的表达和肾癌细胞的迁移。机制分析表明TNF α可诱导肾癌细胞NF-κ B B活化。荧光素酶报告基因分析显示在Rictor启动子区有一个NF-κ B应答元件（-301 ~-51 bp）。染色质免疫沉淀（ChIP）分析进一步证实TNF α诱导p65与Rictor启动子的结合。在异种移植模型中，Rictor的敲低阻断了RCC细胞向小鼠肺和肝的转移。综上所述，我们的研究结果表明，促炎细胞因子TNF α通过NF-κ B途径促进Rictor的表达。
Metastasis accounts for more than 50 % of deaths among renal cell carcinoma (RCC) patients, and therefore, it is important to study the biology of metastasis and identify metastasis-associated biomarkers for risk prognosis and stratification of patients for an individualized therapy of RCC. In cultured RCC cells, knockdown of Rictor by short hairpin RNA (shRNA) inhibited cell migration and invasion, probably due to impairments in activation of Akt. Pretreatment with tumor necrosis factor alpha (TNF alpha) or interleukin 6 (IL-6) enhanced the expression of Rictor and the migration of renal cancer cells. Mechanistic analysis showed that TNF alpha induced the activation of NF-kappa B in RCC cells. Luciferase reporter analysis revealed a NF-kappa B responding element (-301 to -51 bp) at the promoter region of Rictor. Chromatin immunoprecipitation (ChIP) analysis further confirmed that TNF alpha-induced binding of p65 with the promoter of Rictor. In a xenograft model, knockdown of Rictor-blocked RCC cells metastasis to the mouse lungs and livers. Taken together, our results suggest that the proinflammatory cytokine TNF alpha promotes the expression of Rictor through the NF-kappa B pathway.