MTDH promotes metastasis of clear cell renal cell carcinoma by activating SND1-mediated ERK signaling and epithelial-mesenchymal transition
MTDH promotes metastasis of clear cell renal cell carcinoma by activating SND1-mediated ERK signaling and epithelial-mesenchymal transition
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MTDH通过激活SND1介导的ERK信号和上皮间质转化促进透明细胞肾细胞癌的转移
DOI：
10.18632/aging.102694
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发表时间：
2020-01-31
期刊：
影响因子：
5.2
通讯作者：
Zhou, Liqun
中科院分区：
文献类型：
--
作者：
He, Anbang;He, Shiming;Zhou, Liqun
背景：转移是肾细胞癌相关死亡的主要原因。Metadherin（MTDH）被鉴定为参与各种类型肿瘤转移进展的重要转移驱动因子，表明MTDH是预后转移生物标志物和潜在的治疗靶点。MTDH在肾细胞癌转移过程中的作用和机制尚未得到充分探讨。结果：与正常肾组织相比，肾细胞癌组织中MTDH明显升高，尤其是在转移性肾细胞癌组织中，MTDH的表达与肾细胞癌的临床病理特征和预后有关。MTDH激活ERK信号和EMT，从而促进ccRCC细胞的迁移和侵袭。MTDH和SND 1在蛋白质水平上的相互作用通过免疫沉淀和免疫荧光证实。基于GEO和TCGA数据集的分析，SND 1在ccRCC中显著增加，特别是在转移性ccRCC中，并且与晚期临床病理特征和不良预后相关。结论：MTDH可能是ccRCC的一个预后转移生物标志物，它通过激活SND 1介导的ERK和EMT信号通路促进ccRCC的转移。方法：应用R软件包对GEO-ccRCC和TCGA-KIRC数据集进行分析，综合评价MTDH/SND 1 mRNA在肾透明细胞癌（ccRCC）中的表达。通过免疫组织化学（IHC）评估了来自北京大学第一医院的总共111例ccRCC患者中MTDH蛋白的表达。进行了体外迁移和侵袭测定，并开发了体内转移小鼠模型以研究MTDH在ccRCC细胞中的生物学功能。采用相关性分析、免疫沉淀、免疫印迹和免疫荧光等方法探讨肾细胞癌MTDH的分子机制。
Background: Metastasis is the principal cause of renal cell carcinoma-associated mortality. Metadherin (MTDH) was identified as a vital metastasis driver involved in the metastatic progression of various types of tumors, suggesting that MTDH is a prognostic metastatic biomarker and potential therapeutic target. The role and mechanism of MTDH in the metastatic progression of ccRCC have not yet been adequately explored.Results: MTDH was remarkably elevated in ccRCC tissues, especially in metastatic ccRCC tissues, compared with normal kidney tissues and correlated with advanced clinicopathological features and poor prognosis. MTDH activated ERK signaling and EMT, thus promoting the migration and invasion of ccRCC cells. The interaction between MTDH and SND1 at the protein level was confirmed using immunoprecipitation and immunofluorescence. Based on the analysis of datasets from GEO and TCGA, SND1 was remarkably increased in ccRCC, especially in metastatic ccRCC, and associated with advanced clinicopathological features and poor prognosis. Knockdown of SND1 mainly abolished the migration and invasion of ccRCC cells by blocking MTDH-mediated ERK and EMT signaling activation.Conclusion: These results revealed that MTDH may be a prognostic metastatic biomarker of ccRCC that promotes ccRCC metastasis by activating SND1-mediated the ERK and EMT signaling pathways. MTDH may serve as an anti-tumor therapeutic target that can be applied for the clinical treatment of metastatic ccRCC.Methods: MTDH/SND1 mRNA expression in clear cell renal cell carcinoma (ccRCC) was comprehensively estimated by analysis of GEO-ccRCC and TCGA-KIRC datasets with R software and packages. MTDH protein expression was assessed in a total of 111 ccRCC patients from Peking University First Hospital by immunohistochemistry (IHC). In vitro migration and invasion assays were carried out, and an in vivo metastatic mouse model was developed to investigate the biological functions of MTDH in ccRCC cells. Correlation analysis, immunoprecipitation, western blotting and immunofluorescence were applied to explore the molecular mechanisms of MTDH in ccRCC.