TGIF2 promotes the progression of lung adenocarcinoma by bridging EGFR/RAS/ERK signaling to cancer cell stemness  

作　　者：Renle Du Wenzhi Shen Yi Liu Wenjuan Gao Wei Zhou Jun Li Shuangtao Zhao Chong Chen Yanan Chen Yanhua Liu Peiqing Sun Rong Xiang Yi Shi Yunping Luo 

机构地区：[1]Department of Immunology,School of Medicine,Nankai University,Tianjin,300071,China [2]Department of Pathology and Institute of Precision Medicine,Jining Medical University,Jining,272067,China [3]Department of Immunology,Institute of Basic Medical Science,Chinese Academy of Medical Science,School of Basic Medicine,Peking Union Medical College,Beijing,100005,China [4]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education,Tianjin,300071,China [5]Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation,Tianjin,300071,China [6]Department of Cancer Biology,School of Medicine,Wake Forest University,Winston-Salem,NC,27157,USA

出　　处：《Signal Transduction and Targeted Therapy》2019年第1期104-115,共12页信号转导与靶向治疗（英文）

基　　金：This work was supported by the National Natural Science Foundation of China(No.81772974 to Y.Shi,No.1672914 to Y.Luo,and No.81972795 to C.Chen).

摘　　要：TGF-β-induced factor homeobox 2(TGIF2)is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions.Aberrant expression of TGIF family proteins has been observed in several cancers,including ovarian,esophageal,and colorectal cancers.Here,we report that TGIF2 mediates the EGFR–RAS–ERK signaling pathway to enhance the stemness of lung adenocarcinoma(LUAD)cells and,therefore,promote the progression and metastasis of LUAD.We found that high TGIF2 expression was closely correlated with tumor growth,lymph node metastasis,and survival of patients with LUAD.Mice bearing TGIF2-silenced H1299 xenografts developed smaller tumors and fewer lung metastases.Importantly,silencing TGIF2 decreased the cancer stem cell(CSC)-like properties in A549 and H1299 cells.Furthermore,we identified that TGIF2 binding to the OCT4 promoter promotes its expression.In both LUAD cells and in vivo LUAD mouse models,we revealed that EGFR–RAS–ERK signaling phosphorylated TGIF2 and increased its stability,which was important for TGIF2-promoted LUAD stemness since phosphorylation-deficient TGIF2 mutants lost these functions.Thus,our study revealed that an important factor,TGIF2,bridges EGFR signaling to the CSC characteristics of LUAD cells,which can be utilized as an effective target for LUAD therapy.

关 键 词：TGIF ADENOCARCINOMA metastasis 

分 类 号：R73[医药卫生—肿瘤]