Activation of PAX3-MET pathways due to miR-206 loss promotes gastric cancer metastasis.
Activation of PAX3-MET pathways due to miR-206 loss promotes gastric cancer metastasis.
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DOI：
10.1093/carcin/bgv009
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发表时间：
2015-03
期刊：
影响因子：
4.7
通讯作者：
Lin Zhang;L. Xia;Lina Zhao;Zhangqian Chen;X. Shang;J. Xin;Muhan Liu;Xuegang Guo;Kaichun Wu;Yanglin Pan;D. Fan
中科院分区：
文献类型：
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作者：
Lin Zhang;L. Xia;Lina Zhao;Zhangqian Chen;X. Shang;J. Xin;Muhan Liu;Xuegang Guo;Kaichun Wu;Yanglin Pan;D. Fan
MicroRNAs （miRNAs）被认为通过调节多种细胞通路在肿瘤转移中起重要作用。在这里，我们描述了miR-206在胃癌（GC）转移中的功能和调控网络。MiR-206在GC细胞中表达下调，特别是在高转移潜力细胞中，并且在转移灶中与相应的原发肿瘤样本相比，MiR-206的表达也显著降低。功能获得和功能丧失研究均证实，miR-206在体外和体内均能显著抑制GC细胞的侵袭和转移。在机制上，配对盒基因3 （PAX3）被鉴定为GC细胞中miR-206的功能靶点。MiR-206通过负调控PAX3的表达抑制胃癌转移。此外，PAX3在胃癌组织中的表达明显高于癌旁非癌组织。PAX3阳性表达的胃癌患者总生存时间较短。Transwell实验和体内转移实验表明，过表达PAX3可显著促进胃癌细胞的侵袭性和肺转移。另一方面，下调PAX3可显著降低细胞转移潜能。机制研究表明，PAX3的促转移功能是通过上调下游靶点MET介导的。此外，我们发现PAX3和MET水平在匹配的人类GC标本中呈正相关，并且它们的共表达与不良预后相关。总之，我们的研究结果表明，miR-206-PAX3-MET信号在胃癌转移中起着至关重要的作用。靶向本文描述的途径可能为限制胃癌转移潜力开辟新的治疗前景。
MicroRNAs (miRNAs) are thought to have an important role in tumor metastasis by regulating diverse cellular pathways. Here, we describe the function and regulation network of miR-206 in gastric cancer (GC) metastasis. MiR-206 expression was downregulated in GC cells especially in high metastatic potential cells and was also significantly decreased in metastatic lesions compared with their corresponding primary tumor samples. Both gain- and loss-of-function studies confirmed that miR-206 significantly suppressed GC cell invasion and metastasis both in vitro and in vivo. Mechanistically, paired box gene 3 (PAX3) was identified as a functional target of miR-206 in GC cells. MiR-206 inhibited GC metastasis by negatively regulating expression of PAX3. In addition, PAX3 expression was markedly higher in GC tissues than in adjacent non-cancerous tissues. GC patients with positive PAX3 expression had shorter overall survival times. Transwell assays and in vivo metastasis assays demonstrated that overexpression of PAX3 significantly promoted the invasiveness and pulmonary metastasis of GC cells. On the other hand, downregulation of PAX3 markedly reduced cell metastatic potential. Mechanistic investigations indicated that prometastasis function of PAX3 was mediated by upregulating downstream target MET. Moreover, we found that levels of PAX3 and MET were positively correlated in matched human GC specimens, and their coexpression was associated with poor prognoses. In conclusion, our results reveal that miR-206-PAX3-MET signaling is critical to GC metastasis. Targeting the pathway described here may open new therapeutic prospects to restrict the metastatic potential of GC.