Mir-20a-5p induced WTX deficiency promotes gastric cancer progressions through regulating PI3K/AKT signaling pathway.
Mir-20a-5p induced WTX deficiency promotes gastric cancer progressions through regulating PI3K/AKT signaling pathway.
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Mir-20a-5p诱导的WTX缺乏通过调节PI3K/AKT信号通路促进胃癌进展
DOI：
10.1186/s13046-020-01718-4
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发表时间：
2020-10-08
期刊：
影响因子：
--
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Li J;Ye D;Shen P;Liu X;Zhou P;Zhu G;Xu Y;Fu Y;Li X;Sun J;Xu J;Zhang Q
X连锁基因WTX（也称为AMER 1）已被报道在Wilms肿瘤中作为肿瘤抑制基因发挥作用。在我们以前的研究中，WTX表达在胃癌（GC）中显着降低，但与WTX丢失相关的功能和机制尚未完全阐明。进一步分析WTX在胃癌和对照正常胃组织中的表达及其临床意义，并在公共数据库中进行验证。通过KEGG通路分析寻找WTX调控胃癌进展的候选通路。利用微RNA芯片技术筛选监测WTX表达的miRNA。在体外和体内验证该通路和miRNA后，通过Western blot、免疫组化、RT-PCR、免疫共沉淀（Co-IP）和荧光素酶分析等方法分析miRNA、WTX和下游通路的关系。结果表明，WTX在胃癌中是一个抑癌基因。WTX的丢失通过促进GC细胞体外增殖和体内高转移而与GC的侵袭性相关。此外，WTX表达与胃癌患者的总生存率呈正相关。微阵列分析、生物信息学分析和验证实验表明，WTX丢失激活PI 3 K/AKT/mTOR通路，促进GC细胞增殖和侵袭。胃癌中miR-20 a-5 p的异常上调导致WTX丢失，从而刺激PI 3 K磷酸化，激活PI 3 K/AKT/mTOR信号通路，促进胃癌的进展。本研究的结果阐明了GC进展的机制，其至少部分是由异常miR-20 a-5 p上调导致WTX表达抑制和PI 3 K/AKT/mTOR信号通路激活引起的。这些发现提供了对miR-20 a-5 p/WTX/PI 3 K/AKT/mTOR信号通路在GC进展和转移中的作用的全面理解。
The 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. WTX 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. The 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. The 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.
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