Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.
Cancer Cell. 2010 Oct 19;18(4):303-15. doi: 10.1016/j.ccr.2010.09.007.
The global impairment of mature microRNAs (miRNAs) is emerging as a common feature of human tumors. One interesting scenario is that defects in the nuclear export of precursor miRNAs (pre-miRNAs) might occur in transformed cells. Exportin 5 (XPO5) mediates pre-miRNA nuclear export and herein we demonstrate the presence of XPO5-inactivating mutations in a subset of human tumors with microsatellite instability. The XPO5 genetic defect traps pre-miRNAs in the nucleus, reduces miRNA processing, and diminishes miRNA-target inhibition. The XPO5 mutant form lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and pre-miRNAs accumulate in the nucleus. Most importantly, the restoration of XPO5 functions reverses the impaired export of pre-miRNAs and has tumor-suppressor features.
成熟 microRNAs（miRNAs）的全球功能障碍正成为人类肿瘤的共同特征。一种有趣的情况是，前体 miRNA（pre-miRNA）的核输出缺陷可能发生在转化细胞中。Exportin 5（XPO5）介导 pre-miRNA 的核输出，我们在此证明，具有微卫星不稳定性的人类肿瘤亚群中存在 XPO5 失活突变。XPO5 遗传缺陷将 pre-miRNA 困在核内，减少 miRNA 加工，并降低 miRNA 靶抑制。XPO5 突变体形式缺乏一个 C 末端区域，该区域有助于 pre-miRNA/XPO5/Ran-GTP 三元复合物的形成，并且 pre-miRNA 在核内积累。最重要的是，恢复 XPO5 功能可逆转 pre-miRNA 的输出缺陷，并具有肿瘤抑制特征。
