Chen Haiyang, Wu Xuan, Zhou Hanqiong, He Zhen, Li Hongle, Wang Qiming
Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University Zhengzhou 450008, Henan, P. R. China.
Molecular Pathology Department, Affiliated Oncology Hospital, Zhengzhou University Zhengzhou 450008, Henan, P. R. China.
Am J Transl Res. 2021 Feb 15;13(2):708-718. eCollection 2021.
Tumor necrosis factor α-induced protein 3 (A20) suppresses inflammation by inhibiting the activation of nuclear factor kappa B (NF-κB). The aberrant expression of A20 is reportedly correlated with tumor development in human malignancies, including hepatocellular carcinoma (HCC). Proinflammatory mediators, including tumor necrosis factor α (TNF-α), interleukin-1, and lipopolysaccharide, may induce A20 expression. The present study revealed that epidermal growth factor (EGF) significantly increased A20 mRNA and protein levels in normal hepatic and hepatoma cells via the mitogen-activated protein kinase kinase-1 (MEK1)/mitogen- and stress-activated protein kinase-1 (MSK1)/phosphorylated (p)-p65 (Ser276) signaling pathway. A significant positive correlation was observed between the expression of EGF receptor and A20 in HCC and normal healthy liver tissues. The EGF-induced A20 upregulation was NF-κB-dependent and abolished by either the overexpression of the nuclear factor of a κ light polypeptide gene enhancer in a B-cell inhibitor α or treatment with the NF-κB inhibitor BAY11-7082. However, unlike TNF-α, EGF expression did not result in the upregulation of inflammatory molecules, including intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and monocyte chemoattractant protein-1. These results indicate that EGF preferentially upregulated the protective mediator A20 over proinflammatory factors. To our knowledge, the present study is the first to demonstrate that EGF induced A20 expression by activating the MEK1/MSK1/p-p65 (Ser276) signaling pathway without causing an apparent inflammatory response. These results may further extend our understanding of liver inflammation and tumor development.
肿瘤坏死因子α诱导蛋白3(A20)通过抑制核因子κB(NF-κB)的激活来抑制炎症。据报道,A20的异常表达与包括肝细胞癌(HCC)在内的人类恶性肿瘤的肿瘤发展相关。促炎介质,包括肿瘤坏死因子α(TNF-α)、白细胞介素-1和脂多糖,可能诱导A20表达。本研究表明,表皮生长因子(EGF)通过丝裂原活化蛋白激酶激酶-1(MEK1)/丝裂原和应激激活蛋白激酶-1(MSK1)/磷酸化(p)-p65(Ser276)信号通路显著增加正常肝细胞和肝癌细胞中A20 mRNA和蛋白水平。在HCC和正常健康肝脏组织中,EGF受体的表达与A20之间存在显著正相关。EGF诱导的A20上调是NF-κB依赖性的,并且通过κ轻链多肽基因增强子在B细胞抑制剂α中的核因子过表达或用NF-κB抑制剂BAY11-7082处理而被消除。然而,与TNF-α不同,EGF表达并未导致包括细胞间黏附分子1、血管细胞黏附分子1和单核细胞趋化蛋白-1在内的炎症分子上调。这些结果表明,EGF优先上调保护性介质A20而非促炎因子。据我们所知,本研究首次证明EGF通过激活MEK1/MSK1/p-p65(Ser276)信号通路诱导A20表达,而不会引起明显的炎症反应。这些结果可能会进一步扩展我们对肝脏炎症和肿瘤发展的理解。