YAP1 enhances cell proliferation, migration, and invasion of gastric cancer in vitro and in vivo.
Yes-associated protein 1 (YAP1) plays an important role in the development of carcinomas such as breast, colorectal, and gastric (GC) cancers, but the role of YAP1 in GC has not been investigated comprehensively. The present study strongly suggests that YAP1 and P62 were significantly up-regulated in GC specimens, compared with normal gastric mucosa. In addition, the YAP1high P62high expression was independently associated with poor prognosis in GC (hazard ratio: 1.334, 95% confidence interval: 1.045-1.704, P = 0.021). Stable YAP1 silencing inhibited the proliferation, migration, and invasion of BGC-823 GC cells in vitro and inhibited the growth of xenograft tumor and hematogenous metastasis of BGC-823 GC cells in vivo. The mechanism was associated with inhibited extracellular signal-regulated kinases (ERK)1/2 phosphorylation, elevated E-cadherin protein expression and decreased vimentin protein expression, down-regulated β-catenin protein expression and elevated α-catenin protein expression, and down-regulated long non-coding RNA (lncRNA) expressions including HOX transcript antisense RNA (HOTAIR), H19, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), human large tumor suppressor-2 (LATS2)-AS1-001, and LATS2. YAP1 over-expression promoted the proliferation, migration, and invasion of human immortalized normal gastric mucosa GES-1 cells in vitro by reversing the above signal molecules. Subcutaneous inoculation of GES-1 cells and YAP1-over-expressing GES-1 cells into nude mice did not generate tumors. We successfully established the xenograft tumor models using MKN-45 GC cells, but immunochemistry showed that there was no YAP1 expression in MKN-45 cells. These results suggest that YAP1 is not a direct factor affecting tumor formation, but could accelerate tumor growth and metastasis. Collectively, this study highlights an important role for YAP1 as a promoter of GC growth and metastasis, and suggests that YAP1 could possibly be a potential treatment target for GC.
Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Dan
D
Sun
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, China.
Xiaoting
X
Li
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, China.
Yingjian
Y
He
Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Wenhui
W
Li
Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Ying
Y
Wang
Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Huan
H
Wang
Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Shanshan
S
Jiang
Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Yan
Y
Xin
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014746:Vimentin; D000091102:YAP-Signaling Proteins; D051178:alpha Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C094335:H19 long non-coding RNA; C561566:HOTAIR long untranslated RNA, human; C557041:MALAT1 long non-coding RNA, human; C489427:MYC protein, human; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014746:Vimentin; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051178:alpha Catenin; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
gastric cancer; invasion; migration; proliferation; yes-associated protein1/YAP1