MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)
MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)
复制标题
DOI：
10.1073/pnas.1015541107
复制
发表时间：
2010-12-07
影响因子：
11.1
通讯作者：
Croce, Carlo M.
中科院分区：
文献类型：
--
作者：
Valeri, Nicola;Gasparini, Pierluigi;Croce, Carlo M.
MicroRNA-21(miR-21)的过度表达与包括结直肠癌在内的许多人类肿瘤有关，其中似乎调节肿瘤抑制基因的表达，包括p21、磷酸酶和张力蛋白同系物、转化生长因子β受体II和B细胞白血病/淋巴瘤2相关的X蛋白。在这里，我们证明miR-21靶向并下调核心错配修复(MMR)识别蛋白复合体，人MutS同源2(HMSH2)和6(HMSH6)。高表达miR-21的结直肠肿瘤表现为hMSH2蛋白表达减少。过量产生miR-21的细胞显着减少了5-氟尿嘧啶(5-FU)诱导的G2/M损伤、停滞和凋亡，这是核心MMR组件缺陷的特征。此外，异种移植研究表明miR-21过表达显著降低了5-FU的治疗效果。这些研究表明，与miR-21过度表达相关的MMR突变子基因下调可能是结直肠癌治疗效果的重要临床指标。
The overexpression of microRNA-21 (miR-21) is linked to a number of human tumors including colorectal cancer, where it appears to regulate the expression of tumor suppressor genes including p21, phosphatase and tensin homolog, TGF beta receptor II, and B-cell leukemia/lymphoma 2 -associated X protein. Here we demonstrate that miR-21 targets and down-regulates the core mismatch repair (MMR) recognition protein complex, human mutS homolog 2 (hMSH2) and 6 (hMSH6). Colorectal tumors that express a high level of miR-21 display reduced hMSH2 protein expression. Cells that overproduce miR-21 exhibit significantly reduced 5-fluorouracil (5-FU)-induced G2/M damage arrest and apoptosis that is characteristic of defects in the core MMR component. Moreover, xenograft studies demonstrate that miR-21 overexpression dramatically reduces the therapeutic efficacy of 5-FU. These studies suggest that the down-regulation of the MMR mutator gene associated with miR-21 overexpression may be an important clinical indicator of therapeutic efficacy in colorectal cancer.