CYP2E1 overexpression in hepatocellular carcinoma modulates tumor invasion and migration via Wnt/β-catenin signaling pathway.

IF 2.9 4区 生物学 Q3 CELL BIOLOGY
Sharmeen Ishteyaque, Karan Singh Yadav, Shobhit Verma, Arpon Biswas, Rabi Sankar Bhatta, Madhav Nilakanth Mugale
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引用次数: 0

Abstract

Hepatocellular carcinoma (HCC) is the primary cause of cancer-related mortality in the world. Cytochrome P450 2E1 (CYP2E1) plays a key role in metabolizing xenobiotics and toxic substances. The attempts to target CYP2E1 with inhibitors have yielded limited success in cancer treatment. Loss and gain-of-function experiments were performed to investigate the effects of CYP2E1 on HepG2 and Hepa 1-6 cells. Migration, invasion, intracellular reactive oxygen species (ROS) accumulation, and mitochondrial membrane potential were assessed in HepG2 cells. In vivo histopathological alterations were studied in DEN-administered rat models. Western blotting was performed to evaluate the mechanistic activation of the Wnt/β-catenin signaling pathway. In our pursuit, to elucidate the impact of CYP2E1 in carcinogenesis we revealed that in vitro, overexpression of CYP2E1 enhances the migration, invasion, increases the accumulation of intracellular ROS, and reduces the loss of mitochondrial membrane potential of HepG2 cells. In contrast, siRNA-mediated silencing of CYP2E1 produced the opposite effects. Histopathological analysis of liver sections showed pathological features such as clear cell foci, bile duct proliferation, inflammatory cell infiltration and nodule formation. In vitro and in vivo, mechanistic analysis demonstrated that CYP2E1 overexpression significantly activated the Wnt/β-catenin signaling pathway in HCC cells, as evidenced by increased protein levels of β-catenin, LEF, Cyclin D1 and survivin in immunoblot study. In vivo increased β catenin, LEF and GPC3 enhance the carcinogenicity as revealed in immunohistochemistry results. Altogether, the above findings indicates that CYP2E1 has a pivotal role in the pathogenesis and progression of HCC identifying it as a potential target for liver cancer treatment.

肝癌组织中CYP2E1过表达通过Wnt/β-catenin信号通路调控肿瘤侵袭和迁移
肝细胞癌(HCC)是世界上癌症相关死亡的主要原因。细胞色素P450 2E1 (CYP2E1)在代谢外源性和有毒物质中起关键作用。用抑制剂靶向CYP2E1的尝试在癌症治疗中取得了有限的成功。通过功能缺失和功能获得实验研究CYP2E1对HepG2和Hepa 1-6细胞的影响。研究了HepG2细胞的迁移、侵袭、细胞内活性氧(ROS)积累和线粒体膜电位。在给药den的大鼠模型中研究了体内组织病理学改变。Western blotting检测Wnt/β-catenin信号通路的激活机制。在我们的研究中,为了阐明CYP2E1在癌变中的影响,我们在体外发现,CYP2E1的过表达增强了HepG2细胞的迁移、侵袭,增加了细胞内ROS的积累,并减少了线粒体膜电位的丧失。相反,sirna介导的CYP2E1沉默产生相反的效果。肝切片组织病理分析显示细胞灶透明、胆管增生、炎症细胞浸润、结节形成等病理特征。体外和体内机制分析表明,CYP2E1过表达可显著激活HCC细胞中Wnt/β-catenin信号通路,免疫印迹研究显示β-catenin、LEF、Cyclin D1和survivin蛋白水平升高。免疫组化结果显示,体内β catenin、LEF和GPC3升高可增强致癌性。综上所述,上述发现表明CYP2E1在HCC的发病和进展中具有关键作用,是肝癌治疗的潜在靶点。
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来源期刊
Journal of Molecular Histology
Journal of Molecular Histology 生物-细胞生物学
CiteScore
5.90
自引率
0.00%
发文量
68
审稿时长
1 months
期刊介绍: The Journal of Molecular Histology publishes results of original research on the localization and expression of molecules in animal cells, tissues and organs. Coverage includes studies describing novel cellular or ultrastructural distributions of molecules which provide insight into biochemical or physiological function, development, histologic structure and disease processes. Major research themes of particular interest include: - Cell-Cell and Cell-Matrix Interactions; - Connective Tissues; - Development and Disease; - Neuroscience. Please note that the Journal of Molecular Histology does not consider manuscripts dealing with the application of immunological or other probes on non-standard laboratory animal models unless the results are clearly of significant and general biological importance. The Journal of Molecular Histology publishes full-length original research papers, review articles, short communications and letters to the editors. All manuscripts are typically reviewed by two independent referees. The Journal of Molecular Histology is a continuation of The Histochemical Journal.
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