TMEM106A transcriptionally regulated by promoter methylation is involved in invasion and metastasis of hepatocellular carcinoma.
TMEM106A transcriptionally regulated by promoter methylation is involved in invasion and metastasis of hepatocellular carcinoma.
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启动子甲基化转录调控TMEM106A参与肝细胞癌的侵袭和转移
DOI：
10.3724/abbs.2022069
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发表时间：
2022-07-25
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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作者：
据报道，跨膜蛋白106 A（TMEM 106 A）的表达在几种类型的癌症中失调。然而，TMEM 106 A在肝细胞癌（HCC）中的作用仍然未知。在本研究中，我们证明了TMEM 106 A在HCC中与正常肝组织相比显著下调。特别地，在来自HCC患者的肿瘤组织中经常观察到TMEM 106 A的肿瘤特异性DNA甲基化。免疫组织化学和焦磷酸测序揭示了TMEM 106 A甲基化和蛋白表达下调之间的显著关系。受试者工作特征（ROC）曲线分析显示TMEM 106 A在肝癌患者肿瘤组织和癌旁组织中的甲基化存在差异。此外，具有TMEM 106 A高甲基化的HCC患者具有较差的临床预后。5-氮杂-2 ′-脱氧胞苷处理高转移性肝癌细胞中高甲基化的TMEM 106 A增加了TMEM 106 A的表达。功能分析显示，TMEM 106 A的过表达在体外显著抑制HCC细胞的恶性行为，并且在体内降低致瘤性和肺转移。TMEM 106 A通过灭活Erk 1/2/Slug信号通路抑制HCC细胞的上皮间质转化（EMT）。总之，我们的研究结果表明，TMEM 106 A是HCC EMT和转移的抑制剂，并且TMEM 106 A通常通过启动子甲基化而转录下调，这导致TMEM 106 A蛋白水平降低，并预测HCC患者的生存结局较差。
Expression of transmembrane protein 106A (TMEM106A) has been reported to be dysregulated in several types of cancers. However, the role of TMEM106A in hepatocellular carcinoma (HCC) is still unknown. In the present study, we demonstrate that TMEM106A is markedly downregulated in HCC compared with normal liver tissue. In particular, tumor-specific DNA methylation of TMEM106A is frequently observed in tumor tissues from HCC patients. Immunohistochemistry and pyrosequencing reveal a significant relationship between TMEM106A methylation and downregulation of protein expression. Receiver operating characteristic (ROC) curve analysis reveals that methylation of TMEM106A in tumor samples is different from that in non-malignant adjacent tissues of HCC patients. Moreover, HCC patients with TMEM106A hypermethylation have a poor clinical prognosis. 5-Aza-2′-deoxycytidin treatment of hypermethylated TMEM106A in highly metastatic HCC cells increases the expression of TMEM106A. Functional assays reveal that overexpression of TMEM106A significantly suppresses the malignant behavior of HCC cells in vitro and decreases tumorigenicity and lung metastasis in vivo. Mechanistically, TMEM106A inhibits epithelial mesenchymal transition (EMT) of HCC cells through inactivation of the Erk1/2/Slug signaling pathway. In conclusion, our findings demonstrate that TMEM106A is an inhibitor of HCC EMT and metastasis, and TMEM106A is often transcriptionally downregulated by promoter methylation, which results in reduced levels of TMEM106A protein and predicts poor survival outcomes for HCC patients.