Epigenetic inactivation of LHX6 mediated microcystin-LR induced hepatocarcinogenesis via the Wnt/β-catenin and P53 signaling pathways
Epigenetic inactivation of LHX6 mediated microcystin-LR induced hepatocarcinogenesis via the Wnt/β-catenin and P53 signaling pathways
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LHX6 介导的微囊藻毒素-LR 表观遗传失活通过 Wnt/β-catenin 和 P53 信号通路诱导肝癌发生。
DOI：
10.1016/j.envpol.2019.05.049
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发表时间：
2019-09-01
影响因子：
8.9
通讯作者：
Liu, Wen-bin
中科院分区：
文献类型：
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作者：
Chen, Hong-qiang;Zhao, Ji;Liu, Wen-bin
微囊藻毒素(MC)已被动物和细胞实验证明具有致癌性，并通过流行病学研究发现与人类肝细胞癌(HCC)的发生有关。然而，微囊藻毒素-LR(MC-LR)诱导肝癌的分子机制尚不清楚。本研究旨在阐明LHX6在MC-LR诱导的肝癌发生中的作用和机制。利用已建立的MC-LR诱导L02细胞恶性转化模型，筛选出同源异型盒基因LHX6。结果发现，在MC-LR处理的L02细胞中，LHX6的表达显著下调；MC-LR高剂量染毒组大鼠肝组织中LHX6的表达明显下调。在MC-LR处理的L02细胞中，LHX6高甲基化，经10 mU M的5-氮杂-2‘-脱氧胞苷处理后，LHX6的表达上调。此外，LHX6过表达抑制了恶性转化的L02细胞在体内外的增殖、侵袭和迁移，而LHX6过表达则导致相反的表型。此外，我们还发现，P53和Bax的上调导致了细胞的凋亡，而CTNNB1和MMP7的下调导致了MC-LR处理的L02细胞的迁移。用其抑制剂阻断P53和CTNNB1可显著减弱LHX6的作用。在MC-LR诱导的肝癌发生过程中，这些基因共同发挥作用。本研究首次证实LHX6基因表达受DNA甲基化调控，并通过Wnt/β-catenin和p53信号通路抑制MC-LR诱导的肝癌发生过程中的增殖、侵袭和迁移。这一结果提示LHX6基因可作为肝癌治疗的潜在靶基因和生物标志物。(C)2019爱思唯尔有限公司。保留所有权利。
Microcystins (MCs) have been shown to be carcinogenic by animal and cellular experiments and found to be associated with the development of human hepatocellular carcinoma (HCC) through epidemiological studies. However, the molecular mechanism of microcystin-LR (MC-LR) induced HCC is still unclear. This study is determined to clarify the role and mechanism of LHX6 in MC-LR-induced hepatocarcinogenesis. Using the previously established MC-LR-induced malignant transformation model in L02 cells, we screened out LHX6, homeobox gene that was significantly changed. We found that LHX6 was significantly down-regulated in MC-LR treated L02 cells and the liver tissue of rats treated for 35 weeks with 10 mu g/kg body weight of MC-LR Expression of LHX6 in human tumor tissue was significantly down-regulated in high MC-LR-exposure group. LHX6 was hypermethylated in MC-LR treated L02 cells and up-regulated after treatment with 10 mu M of 5-aza-2'-deoxycytidine. Furthermore, overexpression of LHX6 inhibited proliferation, invasion and migration of malignantly transformed L02 cells in vitro and in vivo, while knockdown of LHX6 resulted in an opposite phenotype. In addition, we found that up-regulation of P53 and Bax resulted in apoptosis, and that down-regulation of CTNNB1 and MMP7 led to migration of MC-LR treated L02 cells. Blockade of P53 and CTNNB1 by its inhibitor significantly diminished the effect of LHX6. These genes were working together during the process of MC-LR-induced hepatocarcinogenesis. Our study demonstrated for the first time that LHX6 gene expression is regulated by DNA methylation and can inhibit the proliferation, invasion and migration through Wnt/beta-catenin and P53 signaling pathways during the MC-LR-induced hepatocarcinogenesis. This result may suggest that LHX6 gene can be used as a potential target gene and a biomarker for liver cancer treatment. (C) 2019 Elsevier Ltd. All rights reserved.