title: LKB1 inhibits the proliferation of gastric cancer cells by suppressing the nuclear translocation of Yap and β-catenin.
abstract: Liver kinase B1 (LKB1) is known to suppress the proliferation, energy metabolism and mesenchymal transition of various cancer cells, and is involved in the regulation of Hippo-Yes-associated protein (Yap) and the Wnt/β-catenin signaling pathways. However, the role of LKB1 in gastric cancer (GC) was not fully understood. Thus, in the present study, we studied LKB1 and found that protein expression (0.37±0.061 vs. 0.59±0.108, P=0.006) and the protein ratio of p-Yap/Yap (0.179±0.085 vs. 0.8±0.126, P=0.001) were reduced in 54 gastric adenocarcinoma (GAC) tissues compared with the matched adjacent non-cancerous tissues, using western blotting and RT-qPCR assays. LKB1 expression was also observed decreased in 109 GAC tissues compared with 54 adjacent non-cancerous tissues (χ2=4.678, P=0.0306), and negatively correlated with the nuclear expression of Yap (r=-0.6997) and β-catenin (r=-0.3510), using immunohistochemical analysis. In GC patients, LKB1 expression was negatively associated with tumor size, tumor infiltration, lymph node metastasis and the TNM stage. LKB1 expression was determined to be positively correlated with longer overall survival of GC patients using Kaplan-Meier analysis (P=0.001). Subsequently, LKB1 expression in human GAC AGS cells was enhanced with a full‑length LKB1 transfection. In vitro and in vivo proliferation was inhibited in LKB1-overexpressing GC cells compared with the control cells. Yap and β-catenin expression were assessed by western blotting and RT-qPCR, and were found to be increased in the cytoplasm but decreased in the nucleus in LKB1-overexpressing GC cells compared with the control cells. The increase in cytoplasmic β-catenin was reversed by the silencing of LKB1 or Yap with shRNAs in LKB1-overexpressing GC cells. Moreover, Yap and β-catenin mRNA were barely altered by LKB1 overexpression. Thus, we concluded that LKB1 expression was reduced in GAC tissues but that it correlated positively with better prognosis for GC patients. LKB1 inhibits the proliferation of GC cells by suppressing the nuclear translocation of Yap and β-catenin.
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China.
authors.forename: Lian-Gang
authors.initials: LG
authors.lastname: Ma
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China.
authors.forename: Shi-Bo
authors.initials: SB
authors.lastname: Bian
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Cui
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China.
authors.forename: Hong-Qing
authors.initials: HQ
authors.lastname: Xi
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China.
authors.forename: Ke-Cheng
authors.initials: KC
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China.
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: Qin
authors.affiliation: Institute of Basic Medical Sciences, Chinese People's Liberation Army Academy of Military Medical Sciences, Beijing 100850, P.R. China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism*; D013270:Stomach / Q000473:pathology*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases