MicroRNA-141 inhibits tumor growth and metastasis in gastric cancer by directly targeting transcriptional co-activator with PDZ-binding motif, TAZ.
MicroRNA-141 inhibits tumor growth and metastasis in gastric cancer by directly targeting transcriptional co-activator with PDZ-binding motif, TAZ.
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DOI：
10.1038/cddis.2014.573
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发表时间：
2015-01-29
影响因子：
9
通讯作者：
Zou QM
中科院分区：
文献类型：
--
作者：
Zuo QF;Zhang R;Li BS;Zhao YL;Zhuang Y;Yu T;Gong L;Li S;Xiao B;Zou QM
胃癌（GC）是一种生物学异质性疾病，伴随着多种遗传和表观遗传改变，并且该疾病的分子机制是复杂的并且尚未完全理解。越来越多的证据表明microRNA（miRNA）的异常表达与胃癌的发生有关，但具体的miRNA在胃癌中的作用尚不清楚。MiR-141先前被报道在多种癌症中充当肿瘤抑制因子或致癌基因。然而，它们在胃癌中的准确表达、功能和机制在很大程度上还不清楚。我们发现胃癌组织中miR-141的表达与癌旁正常组织相比显著降低，并且与胃癌患者更具侵袭性的表型显著相关。miR-141模拟物在GC细胞系中的异位表达导致增殖、侵袭和迁移降低，并且在体外抑制GC细胞系中的miR-141促进细胞增殖、侵袭和迁移。我们进一步证明了miR-141在GC中通过靶向PDZ结合基序（TAZ）的转录共激活因子发挥肿瘤抑制作用。此外，在患者和异种移植小鼠中验证了miR-141与其靶点之间的负相关关系。最后，miR-141的过表达抑制了裸鼠的肿瘤生长和肺转移。总之，我们确定miR-141是胃中有效的肿瘤抑制因子，其生长抑制作用部分是通过其下游靶基因TAZ介导的。这些结果提示miR-141可能成为胃癌新的预后标志物和治疗靶点。
Gastric cancer (GC) is a biologically heterogeneous disease accompanying various genetic and epigenetic alterations, and the molecular mechanisms underlying this disease are complex and not completely understood. Increasing evidence shows that abnormal microRNA (miRNA) expression is involved in GC tumorigenesis, but the role of specific miRNAs involved in this disease remains elusive. MiR-141 was previously reported to act as tumor suppressors or oncogenes in diverse cancers. However, their accurate expression, function and mechanism in GC are largely unclear. Here we found that the expression of miR-141 was significantly reduced in GC compared with paired adjacent normal tissues and was significantly correlated with a more aggressive phenotype of GC in patients. Ectopic expression of miR-141 mimics in GC cell lines resulted in reduced proliferation, invasion and migration, and inhibition of miR-141 in GC cell lines promoted cell proliferation, invasion and migration in vitro. We further demonstrated that miR-141 acted as tumor suppressors through targeting transcriptional co-activator with PDZ-binding motif (TAZ) in GC. Moreover, the inverse relationship between miR-141 and its target was verified in patients and xenograft mice. Finally, overexpression of miR-141 suppressed tumor growth and pulmonary metastasis in nude mice. Take together, we identified that miR-141 is a potent tumor suppressor in the stomach, and its growth inhibitory effects are, in part, mediated through its downstream target gene, TAZ. These findings implied that miR-141 might be employed as novel prognostic markers and therapeutic targets of GC.