Oncotarget

Research Papers:

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

Ruo-Chia Tseng _, Jer-Wei Chang, Jiou-Shan Mao, Charng-Dar Tsai, Pei-Chen Wu, Cuei-Jyuan Lin, Yi-Lin Lu, Sheng-You Liao, Hung-Chi Cheng, Han-Shui Hsu and Yi-Ching Wang

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Oncotarget. 2015; 6:44207-44221. https://doi.org/10.18632/oncotarget.6229

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Abstract

Ruo-Chia Tseng1,2,*, Jer-Wei Chang3, Jiou-Shan Mao4, Charng-Dar Tsai1, Pei-Chen Wu1, Cuei-Jyuan Lin2, Yi-Lin Lu5, Sheng-You Liao6, Hung-Chi Cheng7, Han-Shui Hsu8 and Yi-Ching Wang3,6,*

1 Department of Molecular Biology and Human Genetics, College of Life Science, Tzu Chi University, Hualien, Taiwan

2 Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan

3 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan

4 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

5 Department of Life Sciences, National Taiwan Normal University, Taipei, Taiwan

6 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan

7 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

8 Division of Thoracic Surgery, Taipei Veterans General Hospital, Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan

* These authors have contributed equally to this study

Correspondence to:

Ruo-Chia Tseng, email:

Yi-Ching Wang, email:

Keywords: GAS7C, N-WASP, hnRNP U, lung cancer, prognosis

Received: March 07, 2015 Accepted: October 17, 2015 Published: October 25, 2015

Abstract

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 β-catenin protein via the β-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 β-catenin stability via hnRNP U/β-TrCP complex formation. Therefore, GAS7C acts as a metastasis suppressor in lung cancer.


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