MRPL33 and its splicing regulator hnRNPK are required for mitochondria function and implicated in tumor progression
MRPL33 and its splicing regulator hnRNPK are required for mitochondria function and implicated in tumor progression
复制标题
MRPL33 及其剪接调节因子 hnRNPK 是线粒体功能所必需的，并与肿瘤进展有关
DOI：
10.1038/onc.2017.314
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发表时间：
2018-01-04
期刊：
影响因子：
8
通讯作者：
Feng, Y.
中科院分区：
文献类型：
--
作者：
Liu, L.;Luo, C.;Feng, Y.
MRPL 33基因编码一个线粒体体大亚基蛋白，可能参与线粒体翻译。尽管已经描述了MRPL 33的两种剪接变体，但其剪接调控仍然难以捉摸。在这里，我们观察到在一组人类癌细胞中包含选择性外显子3被极大地促进。在癌细胞系和异种移植模型中，含外显子3的MRPL 33长亚型（MRPL 33-L）的缺失导致增殖受损和凋亡增加。MRPL 33-L基因敲低还可诱导线粒体功能障碍，包括活性氧积累增加、ATP产生减少和16 S rRNA水平降低。我们进一步表明，MRPL 33-L前mRNA的选择性剪接受hnRNPK调节，敲低hnRNPK可以表型复制MRPL 33-L缺失。更重要的是，MRPL 33-L的过表达可以增加hnRNPK耗尽的癌细胞的致瘤潜力，这可能表明hnRNPK通过MRPL 33前mRNA的剪接调节介导肿瘤发生。最后，我们发现MRPL 33外显子3的包含在人类结直肠癌组织中得到促进，这与hnRNPK水平相关。总之，我们的研究结果强调了MRPL 33-L和hnRNPK在肿瘤形成中的生物学意义，并将hnRNPK鉴定为癌细胞中MRPL 33前mRNA的关键剪接调节剂。
MRPL33 gene encodes a large mitoribosomal subunit protein, which may be involved in mitochondrial translation. Although two splice variants of MRPL33 have been described, its splicing regulation remains elusive. Here we observed that inclusion of alternative exon 3 was greatly promoted in a panel of human cancer cells. Depletion of the exon 3-containing long isoform of MRPL33 (MRPL33-L) led to impaired proliferation and increased apoptosis in cancer cell lines and in a xenograft model. MRPL33-L knockdown could also induce mitochondrial dysfunction including increased accumulation of reactive oxygen species, decreased ATP production and 16 S rRNA levels. We further showed that alternative splicing of MRPL33-L pre-mRNA is regulated by hnRNPK and that knocking down hnRNPK could phenocopy MRPL33-L depletion. More importantly, overexpression of MRPL33-L could increase tumorigenic potential of hnRNPK-depleted cancer cells, likely indicating that hnRNPK mediates tumorigenesis through splicing regulation of MRPL33 pre-mRNA. Finally, we found that inclusion of MRPL33 exon 3 was promoted in human colorectal cancer tissues and this was correlated with hnRNPK levels. In summary, our findings underscore the biological significance of MRPL33-L and hnRNPK in the tumor formation and identifies hnRNPK as a critical splicing regulator of MRPL33 pre-mRNA in cancer cells.