State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Clin Cancer Res. 2018 Mar 15;24(6):1473-1485. doi: 10.1158/1078-0432.CCR-17-2133. Epub 2017 Dec 29.
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. 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 and Role of RNF6 in modulating SHP-1 expression was examined by coimmunoprecipitation and confocal microscopy, respectively. 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 and RNF6 may activate the JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1. 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. .
E3 泛素连接酶 RNF6（环指蛋白 6）在致癌作用中发挥着关键作用。然而，RNF6 的拷贝数和表达在结直肠癌中很少报道。我们旨在探讨 RNF6 在结直肠癌发生和发展中的机械、生物学和临床作用。从 Tumorscape 和 The Cancer Genome Atlas（TCGA）数据集分析 RNF6 的拷贝数和表达。通过实时 PCR、Western blot 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确定受 RNF6 调节的关键基因。通过检测肿瘤生长和转移的生物学功能，以及通过共免疫沉淀和共聚焦显微镜分别检测 RNF6 调节 SHP-1 表达的作用，来检测 RNF6 的生物学功能。结直肠癌中 RNF6 的拷贝数显著扩增，扩增与 RNF6 的表达水平相关。RNF6 的扩增和过表达与结直肠癌患者的预后不良呈正相关。基因集富集分析（GSEA）显示，在 RNF6 高表达的结直肠癌细胞以及 TCGA 数据集的患者中，富集了与细胞增殖和侵袭相关的基因。下调 RNF6 会损害结肠直肠癌细胞的增殖和侵袭能力，并且 RNF6 可能通过诱导 SHP-1 的泛素化和降解来激活 JAK/STAT3 通路并增加 pSTAT3 水平。基因组扩增导致结直肠癌中 RNF6 的过表达。RNF6 可能是结直肠癌发生的新型生物标志物，并且 RNF6 可能通过促进 SHP-1 泛素化和降解来增加 pSTAT3 水平。靶向 RNF6/SHP-1/STAT3 轴为 RNF6 扩增肿瘤提供了潜在的治疗选择。
