Growth-arrest-specific 7C protein inhibits tumor metastasis via the N-WASP/FAK/F-actin and hnRNP U/β-TrCP/β-catenin pathways in lung cancer

被引：22

作者：

Tseng, Ruo-Chia ^{[1
,2
]}

Chang, Jer-Wei ^{[3
]}

Mao, Jiou-Shan ^{[4
]}

Tsai, Charng-Dar ^{[1
]}

Wu, Pei-Chen ^{[1
]}

Lin, Cuei-Jyuan ^{[2
]}

Lu, Yi-Lin ^{[5
]}

Liao, Sheng-You ^{[6
]}

Cheng, Hung-Chi ^{[7
]}

Hsu, Han-Shui ^{[8
]}

Wang, Yi-Ching ^{[3
,6
]}

机构：

[1] Tzu Chi Univ, Coll Life Sci, Dept Mol Biol & Human Genet, Hualien, Taiwan

[2] Tzu Chi Univ, Inst Med Sci, Hualien, Taiwan

[3] Natl Hlth Res Inst, Inst Mol & Genom Med, Zhunan, Taiwan

[4] Natl Cheng Kung Univ, Coll Med, Dept Pharmacol, Tainan 70101, Taiwan

[5] Natl Taiwan Normal Univ, Dept Life Sci, Taipei, Taiwan

[6] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan 70101, Taiwan

[7] Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol, Tainan 70101, Taiwan

[8] Natl Yang Ming Univ, Sch Med, Inst Emergency & Crit Care Med, Div Thorac Surg,Taipei Vet Gen Hosp, Taipei 112, Taiwan

来源：

ONCOTARGET | 2015年 / 6卷 / 42期

关键词：

GAS7C; N-WASP; hnRNP U; lung cancer; prognosis; BETA-CATENIN; GENE; FIBRONECTIN; GAS7; CELLS; RNA; ASSOCIATION; APOPTOSIS; DOMAINS; REPAIR;

D O I：

10.18632/oncotarget.6229

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Growth-arrest-specific 7 (GAS7) belongs to a group of adaptor proteins that coordinate the actin cytoskeleton. Among human GAS7 isoforms, only GAS7C possesses a Src homology 3 domain. We report here that GAS7C acts as a migration suppressor and can serve as a prognostic biomarker in lung cancer. GAS7C overexpression reduces lung cancer migration, whereas GAS7C knockdown enhances cancer cell migration. Importantly, ectopically overexpressed GAS7C binds tightly with N-WASP thus inactivates the fibronectin/integrin/FAK pathway, which in turn leads to the suppression of F-actin dynamics. In addition, overexpression of GAS7C sequesters hnRNP U and thus decreases the level of beta-catenin protein via the beta-TrCP ubiquitin-degradation pathway. The anti-metastatic effect of GAS7C overexpression was also confirmed using lung cancer xenografts. Our clinical data indicated that 23.6% (25/106) of lung cancer patients showed low expression of GAS7C mRNA which correlated with a poorer overall survival. In addition, low GAS7C mRNA expression was detected in 60.0% of metastatic lung cancer patients, indicating an association between low GAS7C expression and cancer progression. A significant inverse correlation between mRNA expression and promoter hypermethylation was also found, which suggests that the low level of GAS7C expression was partly due to promoter hypermethylation. Our results provide novel evidence that low GAS7C correlates with poor prognosis and promotes metastasis in lung cancer. Low GAS7C increases cancer cell motility by promoting N-WASP/FAK/F-actin cytoskeleton dynamics. It also enhances beta-catenin stability via hnRNP U/beta-TrCP complex formation. Therefore, GAS7C acts as a metastasis suppressor in lung cancer.

引用

页码：44207 / 44221

页数：15

共 37 条

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