| Gastric cancer(GC)is the fourth most common cancer and the third highest cause of cancer-related morality in the world.Despite many years of significant advances in early detection and treatment,the majority of patients with GC are diagnosed at an advanced,unresectable stage,resulting in poor prognosis with a 5-year overall survival rate of only 15%.Therefore,new therapeutic targets,clinical markers and the establishment of more effective therapeutic strategies for GC remain highly desirable.The Hippo signaling pathway is a newly discovered and highly conserved signaling cascade,which regulates organ size and tissue stability by governing cell proliferation and apoptosis.Yes-associated protein(YAP)as the major downstream target of the Hippo pathway,YAP promotes cell proliferation,inhibits cellular apoptosis,and also promotes an epidermal-mesenchymal transition(EMT).Recently,it is reported that YAP is a candidate human oncogene and YAP overexpression or hyperactivation plays a critical role in the development and progression of multiple cancer types,including GC.However,the association of YAP as well as the core components of the Hippo pathway with GC patient survival have not been thoroughly investigated.Although direct mutations affecting the Hippo pathway seem to be uncommon,multiple cancer-associated signalling networks engage in regulatory crosstalk with the Hippo pathway,often at the level of the YAP oncoprotein.The proper regulation of Wnt/?-catenin signaling is crucial for cell proliferation?differentiation?embryo development as well as tissue homeostasis.Mutations in components of this pathway that lead to its hyperactivation are involved in the development of numerous cancers.Growing data indicate that Hippo pathway and Wnt/?-catenin pathway influence each other in a number of ways to properly regulate tissue growth and repair.However,the molecular mechanisms underlying the crosstalk between these two pathways in GC are still not clear.In this study,we assessed the expression patterns of YAP in 28 pairs of GC tumor specimens and adjacent normal tissues by immunohistochemistry.We found a significantly higher expression of YAP(26/28)in tumor tissues in comparison with adjacent normal tissues and YAP was predominantly presented in the nucleus(21/28).The association between YAP as well as the core components of the Hippo pathway expression and GC patient survival and clinicopathologic features was analyzed in the 101 cases of GC tissues.Our results showed that YAP was overexpressed in 75.2 %(76/101)cases of GC and its expression was associated with short overall survival(p=0.001).Moreover,univariate and multivariate Cox regression analyses revealed that YAP expression was an independent prognostic indicator of GC.We also found that the core components of the Hippo pathway Mst1,Lats2 showed a low expression level in GC tissues,whereas the expression level of transcription factor TEAD4 was up-regulated.Specifically,we showed that high YAP expression levels were positively correlated with TEAD4 gene expression but showed an inverse correlation with Mst1 or Lats2 protein level.Furthermore,Kaplan-Meier survival analysis showed that TEAD4 positively expression was a prognostic marker for poor GC survival.Besides,patients with YAP-positive and Mst1/Lats2-negative profiles had worse overall survival.Knockdown YAP expression in GC cells inhibited proliferation,migration,invasion and EMT,but induced apoptosis.We further demonstrated that there was a positive association between YAP and ?-catenin expression levels in GC tissues,and their coexpression correlated with worse overall survival than the other groups.In GC cells,we found that ?-catenin or ?-catenin/TCF4 complexes bind a DNA promoter of the YAP gene to drive YAP expression.In conclusion,our study indicated that YAP overexpression whose expression is driven by aberrant Wnt/?-catenin signaling contributed to the GC tumorigenesis and progression.Therefore,YAP served as an oncogene may be a potential target for GC treatment. |
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