Long Noncoding RNA LINC01485 Promotes Tumor Growth and Migration via Inhibiting EGFR Ubiquitination and Activating EGFR/Akt Signaling in Gastric Cancer

Jianping Zhou1 ,* Lulu Wu1 ,* Weiling Li2 ,* Xiao Xu,1 Feng Ju,1 Shao Yu,1 Jianfeng Guo,3 Gang Li,3 Jun Shi,1 Sujun Zhou1 1Department of Gastrointestinal Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, People’s Republic of China; 2Department of Obstetrics and Gynecology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, People’s Republic of China; 3Department of B-Ultrasound Room, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Sujun Zhou; Jianping ZhouDepartment of Gastrointestinal Surgery, The Affiliated Yixing Hospital of Jiangsu University, No. 75 Tongzhenguan Road, Yixing 214200, Jiangsu, People’s Republic of ChinaTel/ Fax +86-510-87921098Email staff030@yxph.com; staff882@yxph.comBackground: Although several long non-coding RNAs (lncRNAs) have been found to be involved in gastric cancer tumorigenesis, the more comprehensive contributions of lncRNAs to gastric cancer require further investigation. Here, we identify a cytoplasmic lncRNA, LINC01485, which promotes tumor growth and migration in gastric cancer.Materials and Methods: Microarray and computational analysis were utilized to identify differential expression in LINC01485 and EGFR. Real-time PCR and Western blotting assays were used to confirm the expression of LINC01485 and EGFR in gastric cancer cells. Cell proliferation, wound-healing and transwell assays were performed to measure cell growth, migration and invasion. Immunoprecipitation, RNA pull-down, and RNA fluorescence in situ hybridization (RNA-FISH) assays were used to test the interaction of c-Cbl with LINC01485 and EGFR. Furthermore, tumor xenograft in nude mice was performed to test tumor growth in vivo.Results: LINC01485 was upregulated and associated with tumor size, lymphatic metastasis and advanced pathological stage in gastric cancer. LINC01485 promoted gastric cancer cell proliferation, migration and invasion in vitro and in vivo. Furthermore, LINC01485 levels were positively correlated with EGFR expression in gastric cancer tissues and significantly increased the expression and phosphorylation (Tyr1045) of EGFR in gastric cancer cells. Mechanistically, LINC01485 competes with c-Cbl for binding to phosphorylated Tyr1045 site of EGFR, thus interfering with c-Cbl-mediated ubiquitination and subsequent degradation of EGFR.Conclusion: LINC01485 promoted EGFR stabilization and activation of EGFR/Akt signaling in gastric cancer. Our findings illustrate the diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in gastric cancer.Keywords: gastric cancer, long noncoding RNA, LINC01485, EGFR, ubiquitination