miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2
miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2
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miR-26a通过抑制PTEN促进肝细胞癌侵袭和转移并通过抑制EZH2抑制细胞生长
DOI：
10.1038/s41374-019-0270-5
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发表时间：
2019-10-01
影响因子：
5
通讯作者：
Xiao, Dong
中科院分区：
文献类型：
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作者：
Zhao, Wen-Tao;Lin, Xiao-Lin;Xiao, Dong
先前的研究表明，治疗性miR-26 a递送抑制小鼠肝癌模型中的肿瘤发生，而我们发现，强制miR-26 a表达增加肝细胞癌（HCC）细胞迁移和侵袭，这促使我们表征由于异位miR-26 a表达而增强侵袭的原因和机制。功能获得和功能丧失实验表明，miR-26 a在体外促进BEL-7402和HepG 2细胞的迁移和侵袭，并正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-26 a的表达显著增强了HepG 2细胞的体内转移能力。miR-26 a在体外负调控HCC细胞的增殖，并且miR-26 a过表达抑制裸鼠中HepG 2细胞肿瘤的生长。进一步的研究表明，miR-26 a通过抑制甲基转移酶EZH 2抑制细胞生长，通过抑制磷酸酶PTEN促进细胞迁移和侵袭。此外，在有和无转移的HCC标本中，PTEN表达与miR-26 a表达呈负相关。因此，我们的研究结果首次表明，miR-26 a通过抑制PTEN促进侵袭/转移，并通过抑制HCC中的EZH 2抑制细胞增殖。更重要的是，我们的数据还表明，如果miR-26 a将来用作癌症治疗的靶点，则应谨慎。
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.