miR-129 promotes apoptosis and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.
miR-129 promotes apoptosis and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.
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DOI：
10.1038/cddis.2013.193
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发表时间：
2013-06-06
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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基于氟嘧啶的化疗耐药是晚期结直肠癌（CRC）治疗失败的主要原因。肿瘤细胞在基因毒性应激后缺乏凋亡能力是这一内在机制的关键因素。越来越多的证据表明，非编码microrna （mirna）是基因表达的关键调控因子，特别是在急性基因毒性应激下。然而，关于mirna在细胞凋亡中的作用的知识仍然有限。在这项研究中，我们发现了一种由microRNA-129 （miR-129）介导的新机制，通过抑制关键的抗凋亡蛋白b细胞淋巴瘤2 （BCL2）来触发细胞凋亡。miR-129的异位表达促进CRC细胞凋亡，抑制细胞增殖，导致细胞周期阻滞。miR-129触发的内在凋亡通路被caspase-9和caspase-3的切割激活。与配对的正常对照样本相比，CRC组织标本中miR-129的表达明显下调。更重要的是，我们证明了miR-129在体外和体内都增强了5-氟尿嘧啶的细胞毒作用。这些结果表明，miR-129作为肿瘤抑制因子具有独特的潜力，并且是开发基于miR-129的CRC治疗策略的新候选物。
Resistance to fluoropyrimidine-based chemotherapy is the major reason for the failure of advanced colorectal cancer (CRC) treatment. The lack of ability of tumor cells to undergo apoptosis after genotoxic stress is the key contributor to this intrinsic mechanism. Mounting evidence has demonstrated that non-coding microRNAs (miRNAs) are crucial regulators of gene expression, in particular, under acute genotoxic stress. However, there is still limited knowledge about the role of miRNAs in apoptosis. In this study, we discovered a novel mechanism mediated by microRNA-129 (miR-129) to trigger apoptosis by suppressing a key anti-apoptotic protein, B-cell lymphoma 2 (BCL2). Ectopic expression of miR-129 promoted apoptosis, inhibited cell proliferation and caused cell-cycle arrest in CRC cells. The intrinsic apoptotic pathway triggered by miR-129 was activated by cleavage of caspase-9 and caspase-3. The expression of miR-129 was significantly downregulated in CRC tissue specimens compared with the paired normal control samples. More importantly, we demonstrated that miR-129 enhanced the cytotoxic effect of 5-fluorouracil both in vitro and in vivo. These results suggest that miR-129 has a unique potential as a tumor suppressor and a novel candidate for developing miR-129-based therapeutic strategies in CRC.
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