The CRTC1-NEDD9 Signaling Axis Mediates Lung Cancer Progression Caused by LKB1 Loss

被引：44

作者：

Feng, Yan ^{[1
]}

Wang, Ye ^{[1
]}

Wang, Zuoyun ^{[1
]}

Fang, Zhaoyuan ^{[1
]}

Li, Fei ^{[1
]}

Gao, Yijun ^{[1
]}

Liu, Hongyan ^{[1
]}

Xiao, Tian ^{[1
]}

Li, Fuming ^{[1
]}

Zhou, Yang ^{[2
,3
]}

Zhai, Qiwei ^{[4
]}

Liu, Xiaolong ^{[1
]}

Sun, Yihua ^{[5
,6
]}

Bardeesy, Nabeel ^{[7
]}

Wong, Kwok-kin ^{[8
]}

Chen, Haiquan ^{[5
,6
]}

Xiong, Zhi-qi ^{[2
,3
]}

Ji, Hongbin ^{[1
]}

机构：

[1] Chinese Acad Sci, State Key Lab Cell Biol, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China

[2] Chinese Acad Sci, Inst Neurosci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China

[3] Chinese Acad Sci, State Key Lab Neurosci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China

[4] Chinese Acad Sci, Key Lab Nutr & Metab, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai 200031, Peoples R China

[5] Fudan Univ, Dept Thorac Surg, Shanghai Canc Ctr, Shanghai 200433, Peoples R China

[6] Fudan Univ, Dept Oncol, Shanghai Med Coll, Shanghai 200433, Peoples R China

[7] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA

[8] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

来源：

CANCER RESEARCH | 2012年 / 72卷 / 24期

基金：

中国国家自然科学基金;

关键词：

CREB COACTIVATOR TORC2; FILAMENTATION; HUMAN ENHANCER; PROTEIN; EXPRESSION; MUTATIONS; KINASE; GROWTH; IDENTIFICATION; INACTIVATION;

D O I：

10.1158/0008-5472.CAN-12-1909

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Somatic mutation of the tumor suppressor gene LKB1 occurs frequently in lung cancer where it causes tumor progression and metastasis, but the underlying mechanisms remain mainly unknown. Here, we show that the oncogene NEDD9 is an important downstream mediator of lung cancer progression evoked by LKB1 loss. In de novo mouse models, RNAi-mediated silencing of Nedd9 inhibited lung tumor progression, whereas ectopic NEDD9 expression accelerated this process. Mechanistically, LKB1 negatively regulated NEDD9 transcription by promoting cytosolic translocation of CRTC1 from the nucleus. Notably, ectopic expression of either NEDD9 or CRTC1 partially reversed the inhibitory function of LKB1 on metastasis of lung cancer cells. In clinical specimens, elevated expression of NEDD9 was associated with malignant progression and metastasis. Collectively, our results decipher the mechanism through which LKB1 deficiency promotes lung cancer progression and metastasis, and provide a mechanistic rationale for therapeutic attack of these processes. Cancer Res; 72(24); 6502-11. (c) 2012 AACR.

引用

页码：6502 / 6511

页数：10

共 46 条

[31] LKB1 gene mutations in Japanese lung cancer patients [J].