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SHISA2 enhances the aggressive phenotype in prostate cancer through the regulation of WNT5A expression

机译:Shisa2通过调节Wnt5a表达来增强前列腺癌中的侵袭性表型

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摘要

The present study aimed at identifying novel molecular cancer drug targets and biomarkers by analyzing the gene expression profiles of high-grade prostate cancer (PC), using a cDNA microarray combined with laser microbeam microdissection. A number of genes were identified that were transactivated in high-grade PC. First, a novel molecular target and diagnostic biomarker, shisa family member 2 (SHISA2), was identified as an overexpressed gene in high-grade PC cells. The reverse transcription-semi-quantitative polymerase chain reaction and immunohistochemical analysis validated the overexpression of SHISA2 (295 amino acids in length), specifically in high-grade PC cells with Gleason scores of between 8 and 10, relative to normal prostate epithelium. Knockdown of SHISA2 expression by short interfering RNA resulted in the marked suppression of PC cell viability. By contrast, exogenous SHISA2 expression in transfected cells promoted PC cell proliferation, indicating its oncogenic effects. Notably, as a result of cDNA microarray analysis, protein Wnt-5a (WNT5A) was focused upon and the expression of WNT5A was identified to be downregulated in SHISA2-knockdown. Western blot analysis validated significant downregulation of WNT5A by SHISA2-knockdown and upregulation of WNT5A by SHISA2 overexpression. The results of the present study indicated that SHISA2 may affect WNT5A synthesis. Furthermore, the secreted SHISA2 protein was determined in the culture medium of PC cells. We hypothesize that SHISA2 is involved in the regulation of WNT5A and in the aggressiveness of PC via the Wnt signaling pathway through WNT5A. Furthermore, SHISA2 may be a molecular target for cancer drugs, and a useful diagnostic biomarker for the prognosis and therapeutic effect in cancer.
机译:本研究旨在通过分析高级前列腺癌(PC)的基因表达谱,使用CDNA微阵列与激光微辐射微探针结合来鉴定新的分子癌药物靶标和生物标志物。鉴定了许多基因,其在高级PC中转移。首先,将新的分子靶和诊断生物标志物,氏氏Shisa系列构件2(Shisa2)鉴定为高级PC细胞中过表达基因。逆转录半定量聚合酶链反应和免疫组织化学分析验证了Shisa2(长度为295个氨基酸)的过表达,特别是在高级PC细胞中,具有相对于正常前列腺上皮的GLEASON得分为8和10之间。通过短干扰RNA敲低Shisa2表达导致PC细胞活力的显着抑制。相比之下,转染细胞中的外源性Shisa2表达促进了PC细胞增殖,表明其致癌作用。值得注意的是,由于cDNA微阵列分析,蛋白质Wnt-5a(Wnt5a)聚焦并鉴定出Wnt5a的表达在Shisa2-敲低的下调。 Western Blot分析通过Shisa2敲除和Shisa2过表达的Wnt5a敲低的Wnt5a的显着下调。本研究的结果表明,Shisa2可能影响WNT5A合成。此外,在PC细胞的培养基中测定分泌的Shisa2蛋白。我们假设Shisa2参与WNT5a的调节和通过Wnt信号通路通过Wnt5a的Wnt信号传导途径的侵略性。此外,Shisa2可以是癌症药物的分子靶标,以及用于癌症预后和治疗效果的有用诊断生物标志物。

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