Abstract
BackgroundThe X-linked gene WTX (also called AMER1) has been reported to function as a tumour suppressor gene in Wilms’ tumour. In our previous study, WTX expression was shown to be significantly reduced in gastric cancer (GC), but the function and mechanism associated with WTX loss had yet to be fully elucidated.MethodsWTX expression and clinical significance were father analyzed in GC and control normal gastric tissues, and validated in public databases. The candidate pathway which was regulated by WTX during GC progression was searched by KEGG pathway analysis. The miRNA which monitored WTX expression was screened by miRNA microarray. After verified the pathway and miRNA both in vitro and in vivo, the relationship of miRNA, WTX and the downstream pathway were analyzed by Western blot, immunohistochemistry, RT-PCR, Co-immunoprecipitation (Co-IP), and luciferase analyses.ResultsThe results showed that WTX serves as a tumour suppressor gene in GC. The loss of WTX which is associated with the aggressiveness of GC by promoting GC cell proliferation in vitro and high metastasis in vivo. Furthermore, WTX expression was positively correlated with the overall survival of GC patients. Microarray assays, bioinformatics analysis, and verification experiments showed that WTX loss activates the PI3K/AKT/mTOR pathway and promotes GC cell proliferation and invasion. And the aberrant miR-20a-5p upregulation contributes to WTX loss in GC, which stimulates PI3K phosphorylation to activate PI3K/AKT/mTOR signaling pathway and promoted GC progression.ConclusionsThe results of the present study elucidated the mechanism of GC progression, which is at least partially caused by aberrant miR-20a-5p upregulation leading to the inhibition of WTX expression and PI3K/AKT/mTOR signaling pathway activation. These findings provide a comprehensive understanding of the action of the miR-20a-5p/WTX/PI3K/AKT/mTOR signaling pathway in the progression and metastasis of GC.
Highlights
The X-linked gene Wilms tumour gene on the X chromosome (WTX) has been reported to function as a tumour suppressor gene in Wilms’ tumour
WTX loss correlates with GC progression and poor prognosis To investigate the role of WTX in gastric cancer (GC), we performed IHC staining of WTX using 161 cases of GC and matched adjacent normal gastric tissue samples (Fig. 1a)
Positive WTX expression was observed for 15.2% (15/99) of groups with lymph node metastasis and 43.6% (17/39) of groups without lymph node metastasis (P < 0.001, Fig. 1d and Table 1), suggesting that WTX expression is negatively correlated with lymph node metastasis
Summary
The X-linked gene WTX ( called AMER1) has been reported to function as a tumour suppressor gene in Wilms’ tumour. WTX expression was shown to be significantly reduced in gastric cancer (GC), but the function and mechanism associated with WTX loss had yet to be fully elucidated. Because of its unique location, a “one hit” somatic inactivation that targets the single allele in males or the active X allele in females can cause WTX gene inactivation [7]. The results of mechanistic studies have shown that WTX inhibits the WNT/β-catenin signaling pathway activation by binding β-catenin [9]. As a candidate tumour-suppressor gene, the expression and functions of WTX have not been fully elucidated in other tumours
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