Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou, 510515, China.
Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510315, China.
Lab Invest. 2019 Oct;99(10):1484-1500. doi: 10.1038/s41374-019-0270-5. Epub 2019 Jun 14.
A previous study revealed that therapeutic miR-26a delivery suppresses tumorigenesis in a murine liver cancer model, whereas we found that forced miR-26a expression increased hepatocellular carcinoma (HCC) cell migration and invasion, which prompted us to characterize the causes and mechanisms underlying enhanced invasion due to ectopic miR-26a expression. Gain-of-function and loss-of-function experiments demonstrated that miR-26a promoted migration and invasion of BEL-7402 and HepG2 cells in vitro and positively modulated matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, and MMP-10 expression. In addition, exogenous miR-26a expression significantly enhanced the metastatic ability of HepG2 cells in vivo. miR-26a negatively regulated in vitro proliferation of HCC cells, and miR-26a overexpression suppressed HepG2 cell tumor growth in nude mice. Further studies revealed that miR-26a inhibited cell growth by repressing the methyltransferase EZH2 and promoted cell migration and invasion by inhibiting the phosphatase PTEN. Furthermore, PTEN expression negatively correlated with miR-26a expression in HCC specimens from patients with and without metastasis. Thus, our findings suggest for the first time that miR-26a promotes invasion/metastasis by inhibiting PTEN and inhibits cell proliferation by repressing EZH2 in HCC. More importantly, our data also suggest caution if miR-26a is used as a target for cancer therapy in the future.
先前的研究表明，治疗性 miR-26a 递呈可抑制小鼠肝癌模型中的肿瘤发生，而我们发现强制表达 miR-26a 会增加肝细胞癌 (HCC) 细胞的迁移和侵袭，这促使我们对由于异位 miR-26a 表达而导致侵袭增强的原因和机制进行表征。功能获得和功能丧失实验表明，miR-26a 促进 BEL-7402 和 HepG2 细胞的体外迁移和侵袭，并正向调节基质金属蛋白酶 (MMP)-1、MMP-2、MMP-9 和 MMP-10 的表达。此外，外源性 miR-26a 表达显著增强了 HepG2 细胞在体内的转移能力。miR-26a 负调控 HCC 细胞的体外增殖，过表达 miR-26a 抑制裸鼠中 HepG2 细胞的肿瘤生长。进一步的研究表明，miR-26a 通过抑制甲基转移酶 EZH2 抑制细胞生长，并通过抑制磷酸酶 PTEN 促进细胞迁移和侵袭。此外，PTEN 表达与有无转移的 HCC 标本中的 miR-26a 表达呈负相关。因此，我们的研究结果首次表明，miR-26a 通过抑制 PTEN 促进侵袭/转移，并通过抑制 EZH2 抑制 HCC 中的细胞增殖。更重要的是，如果 miR-26a 在未来被用作癌症治疗的靶点，我们的数据也表明需要谨慎。
