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  • br Materials and methods br Results br

    2021-09-02


    Materials and methods
    Results
    Discussion The development of HCC is a multistep process involving the accumulation of multiple genetic and epigenetic alterations that lead to the activation of oncogenes and inactivation of tumor suppressor genes [20]. Frequent intrahepatic or pulmonary metastasis makes predominant contributions to high recurrence and mortality rate of HCC [21] The recurrence and metastasis of HCC was regulated by various factors [22,23]. Despite the recent reports illuminated signaling regulators related to HCC recurrence and metastasis, the underlying signaling network remains largely unknown. MicroRNA-137 was reported as a cancer suppressor gene, which was lowly expressed in various cancers, including HCC, inhibiting cancer proliferation, cell-cycle progression and migration [[10], [11], [12], [13]]. As the molecular mechanisms underlying HCC metastasis remain largely unknown, this study is aiming at identifying novel molecules mechanism responsible for metastasis, and developing a novel strategy to combat with HCC metastasis, which will contribute to improving overall survival (OS) of HCC patients. In this study, we found that miR-137 restrained HCC migration and invasion by targeting EZH2-STAT3 signaling in vitro and in vivo, providing a novel mechanism, miR-137-EZH2-STAT3 signaling, mediated in HCC metastasis. Emerging evidence showed that miR-137 inhibited proliferation, chemo-resistance, prognosis of human HCC. In Sakabe et al.’s study, the representative miRNAs was examined in 110 HCC patients, showing miR-137 may serve as a prognostic marker in patients with HCC and may be a potential target for the elimination of liver CSCs [24]. In Lu et al. reported upregulation of miR-137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in HCC cell line Huh7 AMG 337 synthesis [25]. Tian et al. found that miR-137/miR-133a-TINCR pathway may serve as a promising target for tumor recurrence and prognosis of patients with HCC [26]. Moreover, miR-137 was recently reported as a tumor suppressor in tumor metastasis. Gao et al. reported that miR-137 was upregulated to inhibit cell proliferation and metastasis in vitro and tumor growth in vivo, which was regulated by cell division control protein 42 (CDC42) [27]. However, through which miR-137 involved in the metastasis progression in human HCC remains unclear. In our study, we revealed that EZH2 is downstream target of miR-137 in HCC, and resulting in the HCC migration and invasion. In a wide range of cancers including HCC, EZH2 is highly expressed and its expression positively correlates with tumor malignancy and invasiveness in HCC [15,[28], [29], [30]]. For example, Yang et al. revealed that the mRNA levels of EZH2 in HCC tissues and in Hep3B cells were significantly higher compared with those in normal samples, promoting cell proliferation and invasion [28]. Moreover, it was reported that miR-137 regulated cell proliferation, migration, invasion and angiogenesis by targeting EAH2 in various cancer, such as glioblastoma, melanoma and cervical cancer [16,31,32]. Importantly, miR-137 is significantly lower in primary HCC compared to the non-tumorous tissues, which is negative correlations with the expression of EZH2 in HCC [33]. In our observations, EZH2 is regulated by miR-137 and plays an important role in HCC metastasis, as EZH2 overexpression reverses the miR-137 mimics-induced inhibitory effects on migration and invasion of HCC cells. Recent reports revealed that EZH2 directly targeted STAT3 and activated STAT3 signaling. Kim et al. reported that phosphorylation of EZH2 activated STAT3 signaling via STAT3 methylation and promoted tumorigenicity of glioblastoma stem-like cells [19]. What’s more, NF-YA promoted invasion and angiogenesis by upregulating EZH2-STAT3 signaling in human melanoma cells [34]. Thus, EZH2-STAT3 signaling was widely considered promoting cancer progression. In this study, we also found that miR-137 suppressed EZH2-STAT3 signaling in HCC cells and in vivo lung metastasis model.