Lu Shan, Zhu Qingyi, Zhang Yi, Song Wei, Wilson Michael J, Liu Ping
Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, Life Science College, Nanjing Normal University, Nanjing, Jiangsu, P.R. China.
J Cell Physiol. 2015 Aug;230(8):1862-70. doi: 10.1002/jcp.24914.
MicroRNA-520c (miR-520c) and microRNA-373 (miR-373) are originally characterized as both oncogenes and tumor suppressors in different types of human cancers. In this study, we found that translation of mRNA of MT1-MMP, an oncogene related to tumor metastasis, was well inhibited by miR-520c and miR-373 in several types of human cancer cells. Our experimental data demonstrated that these two microRNAs inhibited the translation of mRNA of MT1-MMP and down-regulated its proteolytic enzyme activities via targeting 3'UTR of mRNA of MT1-MMP, further decreased activating proMMP2 into active MMP2 in fibrosarcoma HT1080, benign prostatic hyperplasia epithelial cell BPH-1 and glioblastoma U87GM. More interestingly, from the effects of microRNAs on cell functions, we found that cell growth were all blocked on fibronectin and type IV collagen coated plates and also in three-dimension type I collagen lattice but enhanced only in HT1080 cells on type IV collagen coated plates and in three-dimension type I collagen lattice; cell migration results showed the same effect as that of cell growth. The difference was due to up-regulating the expression of MMP9 gene by miR-520c and miR-373 in HT1080 cells but not in BPH-1 and U87GM cells. Our findings suggest that miR-520c and miR-373, which have different roles in different type of cancer via regulating the translation of mRNA of MT1-MMP and the expression of MMP9 gene, might have an important clue on clinic when selecting the therapeutic regimen and finding new drugs for intervention in different kinds of cancer.
微小RNA-520c（miR-520c）和微小RNA-373（miR-373）最初在不同类型的人类癌症中既被表征为癌基因，又被表征为肿瘤抑制因子。在本研究中，我们发现，在几种类型的人类癌细胞中，与肿瘤转移相关的癌基因MT1-MMP的mRNA翻译受到miR-520c和miR-373的良好抑制。我们的实验数据表明，这两种微小RNA通过靶向MT1-MMP的mRNA的3'非翻译区（3'UTR）抑制MT1-MMP的mRNA翻译并下调其蛋白水解酶活性，进而在纤维肉瘤HT1080、良性前列腺增生上皮细胞BPH-1和成胶质细胞瘤U87GM中减少前MMP2激活为活性MMP2。更有趣的是，从微小RNA对细胞功能的影响来看，我们发现细胞生长在纤连蛋白和IV型胶原包被的平板上以及三维I型胶原晶格中均受到抑制，但仅在IV型胶原包被的平板上和三维I型胶原晶格中的HT1080细胞中增强；细胞迁移结果与细胞生长结果相同。差异是由于miR-520c和miR-373在HT1080细胞中上调MMP9基因的表达，但在BPH-1和U87GM细胞中未上调。我们的研究结果表明，miR-520c和miR-373通过调节MT1-MMP的mRNA翻译和MMP9基因的表达在不同类型的癌症中发挥不同作用，这可能为临床选择治疗方案和寻找干预不同类型癌症的新药提供重要线索。
