journal contribution
posted on 2023-03-31, 19:08 authored by Qian Liang, Dan Ma, Xiaoqiang Zhu, Zhenhua Wang, Tian-Tian Sun, Chaoqin Shen, Tingting Yan, Xianglong Tian, TaChung Yu, Fangfang Guo, JiaYin Tang, Yanwei Lin, Huimin Chen, Chao Zhou, Zhizheng Ge, Ming Zhong, Jinxian Chen, Qiang Liu, Zheng Wang, Jing-Yuan Fang, Haoyan Chen, Jie Hong <p>Fig. S1. RNF6 genomic amplification is prevalent in colorectal cancer and correlated with shortened patient survival. Fig. S2. RNF6 is clinically relevant in colorectal cancer. Fig. S3. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) in RNF6-higher/lower expression CRC cells and patients, and RNF6 is an oncogenic gene. FigureS4. RNF6 upregulates pSTAT3 via downregulating SHP-1 expression. Figure S5. RNF6 Interacts with SHP-1 and enhances ubiquitylation and degradation of SHP-1. Figure S6. Effectiveness of pSTAT3 inhibitors in treating RNF6-amplified tumors.</p>
Funding
National Natural Science Foundation of China
Program for Professor of Special Appointment
Shanghai Institutions of Higher Learning
Shanghai Municipal Education Commission—Gaofeng Clinical Medicine
Chenxing Project of Shanghai Jiao-Tong University
“Shu Guang” project
Shanghai Sailing Program
“Chen Guang” project
History
ARTICLE ABSTRACT
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.
