MicroRNA-34b inhibits pancreatic cancer metastasis through repressing Smad3.
MicroRNA-34b inhibits pancreatic cancer metastasis through repressing Smad3.
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MicroRNA-34b 通过抑制 Smad3 抑制胰腺癌转移。
DOI：
10.2174/1566524011313040001
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发表时间：
2013-05
影响因子：
2.5
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Long J;Xu J;Li M;Yu X
胰腺癌由于早期复发和转移，预后极差，越来越多的证据支持microRNA在癌症进展中的关键作用。在这里，我们发现microRNA-34b作为一种肿瘤抑制microRNA，在胰腺癌中靶向致癌基因Smad3。miR-34b作为一种具有潜在内质网应激微环境的低血管肿瘤，在胰腺癌细胞中经内质网应激诱导剂thapsigargin （Tg）处理后沉默，并受到内质网应激伴侣葡萄糖调节蛋白78 （GRP78）的负调控。在人体标本中，我们发现miR-34b在胰腺癌组织中下调，miR-34b低水平表达与肿瘤淋巴结转移（TNM）分期、淋巴结转移和总生存率呈正相关。功能分析显示，miR-34b的过表达在体外和体内抑制了胰腺癌的进展。此外，Smad3被证明是miR-34b的直接靶点，并在mRNA和蛋白水平上受到miR-34b的负调控。荧光素酶检测证实miR-34b可以直接结合到Smad3的3'非翻译区。在64个胰腺癌组织中观察到miR-34b与Smad3呈负相关。我们的研究结果表明，miR-34b通过负调节Smad3作为肿瘤转移抑制因子，这可能为胰腺癌提供潜在的治疗策略。
Pancreatic cancer is characterized by extremely poor prognosis because of early recurrence and metastasis, and increasing evidence supports the critical role of microRNA in cancer progression. Here we identified that microRNA-34b functioned as a tumor-suppressing microRNA by targeting oncogenic Smad3 in pancreatic cancer. As a hypovascular tumor with a potential endoplasmic reticulum stress microenvironment, miR-34b was silenced after ER stress inducer thapsigargin (Tg) treatment and negatively regulated by ER stress chaperone glucose regulated protein 78 (GRP78) in pancreatic cancer cells. In human specimens, we found that miR-34b was down-regulated in pancreatic cancer tissues and low level of miR-34b expression was positively correlated with tumor-node-metastasis (TNM) stage, lymph-node metastasis and overall survival. Functional assays showed that over-expression of miR-34b inhibited pancreatic cancer progression in vitro and in vivo. In addition, Smad3 was demonstrated as a direct target of miR-34b and negatively regulated by miR- 34b at mRNA and protein levels. Luciferase assays confirmed that miR-34b could directly bind to the 3'untranslated region of Smad3. An inverse correlation between miR-34b and Smad3 was observed in 64 pancreatic cancer tissues. Our findings indicate that miR-34b acts as a tumor metastasis suppressor through negatively modulating Smad3, which may provide a potential therapeutic strategy for pancreatic cancer.