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.
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.
Department of Molecular Biology and Human Genetics, College of Life Science, Tzu Chi University, Hualien, Taiwan.|Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
Ruo-Chia
RC
Tseng
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Jer-Wei
JW
Chang
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Jiou-Shan
JS
Mao
Department of Molecular Biology and Human Genetics, College of Life Science, Tzu Chi University, Hualien, Taiwan.
Charng-Dar
CD
Tsai
Department of Molecular Biology and Human Genetics, College of Life Science, Tzu Chi University, Hualien, Taiwan.
Pei-Chen
PC
Wu
Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
Cuei-Jyuan
CJ
Lin
Department of Life Sciences, National Taiwan Normal University, Taipei, Taiwan.
Yi-Lin
YL
Lu
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Sheng-You
SY
Liao
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hung-Chi
HC
Cheng
Division of Thoracic Surgery, Taipei Veterans General Hospital, Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Han-Shui
HS
Hsu
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yi-Ching
YC
Wang
D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D003599:Cytoskeleton / Q000201:enzymology / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
D000199:Actins; C471644:BTRC protein, human; C495270:CTNNB1 protein, human; C114909:GAS7 protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009419:Nerve Tissue Proteins; C495771:WASL protein, human; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
GAS7C; N-WASP; hnRNP U; lung cancer; prognosis