Department of Orthopedics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095#, Jiefang Ave, Wuhan, 430030, People's Republic of China.
Cell Death Dis. 2018 May 23;9(6):611. doi: 10.1038/s41419-018-0620-z.
Epidemiological studies have demonstrated that metformin could mitigate the progression of several tumors. Although it has been proved that metformin could cause demethylation of DNA and lead to up-regulation of some encoding genes and non-coding RNAs, there is little data about the effects of metformin on metastasis, and the interaction between metastasis and autophagy in human osteosarcoma cells. Here, we found miR-570-3p was significantly down-regulated in human metastatic osteosarcoma tissues but not in non-metastatic osteosarcoma tissues. Metformin attenuates the metastasis and autophagy in osteosarcoma. Interestingly, this autophagy favors osteosarcoma cells invasion. Moreover, reduction of metformin-induced inhibition of autophagy could reverse the invasion suppression in osteosarcoma. Mechanistically, metformin increases miR-570-3p by the demethylation of DNA, and the upregulation of miR-570-3p repressed the translation of its target, LCMR1 and ATG12. Our results, for the first time, presents evidence that the miR-570-3p-mediated suppression of LCMR1 and ATG12 is involved in the metformin-induced inhibition of metastasis in osteosarcoma cells.
流行病学研究表明，二甲双胍可以减缓多种肿瘤的进展。虽然已经证明二甲双胍可以使 DNA 去甲基化，从而导致一些编码基因和非编码 RNA 的上调，但关于二甲双胍对转移的影响以及人骨肉瘤细胞中转移和自噬之间的相互作用的数据很少。在这里，我们发现 miR-570-3p 在人转移性骨肉瘤组织中显著下调，但在非转移性骨肉瘤组织中没有下调。二甲双胍可减弱骨肉瘤的转移和自噬。有趣的是，这种自噬有利于骨肉瘤细胞的侵袭。此外，减少二甲双胍诱导的自噬抑制可以逆转骨肉瘤侵袭的抑制。从机制上讲，二甲双胍通过 DNA 的去甲基化增加 miR-570-3p，上调 miR-570-3p 抑制其靶标 LCMR1 和 ATG12 的翻译。我们的研究结果首次表明，miR-570-3p 介导的 LCMR1 和 ATG12 抑制参与了二甲双胍抑制骨肉瘤细胞转移。
