RING-Finger Protein 6 Amplification Activates JAK/STAT3 Pathway by Modifying SHP-1 Ubiquitylation and Associates with Poor Outcome in Colorectal Cancer
RING-Finger Protein 6 Amplification Activates JAK/STAT3 Pathway by Modifying SHP-1 Ubiquitylation and Associates with Poor Outcome in Colorectal Cancer
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RING-Finger 蛋白 6 扩增通过修饰 SHP-1 泛素化激活 JAK/STAT3 通路，并与结直肠癌的不良预后相关
DOI：
10.1158/1078-0432.ccr-17-2133
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发表时间：
2018-03-15
影响因子：
11.5
通讯作者：
Hong, Jie
中科院分区：
文献类型：
--
作者：
Liang, Qian;Ma, Dan;Hong, Jie
目的：E3泛素连接酶RNF 6（RING-指蛋白6）在肿瘤发生中起重要作用。然而，RNF 6的拷贝数和表达在结直肠癌中的报道很少。我们的目的是探索RNF 6在结直肠癌发生和发展中的机械，生物学和临床作用。设计：从Tumorscape和癌症基因组图谱（TCGA）数据集分析RNF 6的拷贝数和表达。采用实时荧光定量PCR、免疫印迹和免疫组织化学染色检测基因表达。进行基因表达谱研究以鉴定由RNF 6调控的关键基因。在体内和体外检测RNF 6对肿瘤生长和转移的生物学作用。RNF 6在调节SHP-1表达中的作用分别通过免疫共沉淀和共聚焦显微镜检查。结果：结直肠癌组织中RNF 6基因拷贝数显著扩增，且扩增程度与RNF 6表达水平相关。RNF 6的扩增和过表达与预后不良的结直肠癌患者正相关。基因集富集分析（GSEA）显示细胞增殖，并且侵袭相关基因在RNF 6高表达的结直肠癌细胞以及来自TCGA数据集的患者中富集。RNF 6的下调在体外和体内均损害结直肠癌细胞的增殖和侵袭。RNF 6可能通过诱导SHP-1的泛素化和降解激活JAK/STAT 3通路并增加pSTAT 3水平。结论：基因组扩增驱动RNF 6在结直肠癌中过表达。RNF 6可能是结直肠癌发生的一个新的生物标志物，RNF 6可能通过促进SHP-1泛素化和降解而增加pSTAT 3的表达。靶向RNF 6/SHP-1/STAT 3轴为RNF 6扩增的肿瘤提供了潜在的治疗选择。临床癌症研究; 24（6）; 1473-85。©2017 AACR.
Objective: The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer. We aimed to explore the mechanical, biological, and clinical role of RNF6 in colorectal cancer initiation and progression. Design: The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real-time PCR, Western blot, and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and in vitro. Role of RNF6 in modulating SHP-1 expression was examined by coimmunoprecipitation and confocal microscopy, respectively. Results: The copy number of RNF6 was significantly amplified in colorectal cancer, and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with patients with colorectal cancer with poor prognosis. The gene set enrichment analysis (GSEA) revealed cell proliferation, and invasion-related genes were enriched in RNF6 high-expressed colorectal cancer cells as well as in patients from TCGA dataset. Downregulation of RNF6 impaired the colorectal cancer cell proliferation and invasion in vitro and in vivo. RNF6 may activate the JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1. Conclusions: Genomic amplification drives RNF6 overexpression in colorectal cancer. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP-1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors. Clin Cancer Res; 24(6); 1473–85. ©2017 AACR.