Pu Rui, Liu Wenbin, Zhou Xinyu, Chen Xi, Hou Xiaomei, Cai Shiliang, Chen Liping, Wu Jianfeng, Yang Fan, Tan Xiaojie, Yin Jianhua, Wang Xin, Cao Guangwen
Department of Epidemiology, Second Military Medical University, Shanghai, China.
Department of Pathology, Xijing Hospital, Xi'an, China.
Front Oncol. 2022 Feb 10;12:836517. doi: 10.3389/fonc.2022.836517. eCollection 2022.
We aimed to elucidate the mechanism by which hepatitis B virus X (HBx) mutations increase the occurrence of hepatocellular carcinoma (HCC) and identify novel putative therapeutic targets. Wild-type HBx (WT-HBx) and four HBx mutants (M1, A1762T/G1764A; M2, T1674G+T1753C+A1762T/G1764A; M3, C1653T+T1674G+A1762T/G1764A; and Ct-HBx, carboxylic acid-terminal truncated HBx) were delivered into () mouse models. The HCC incidence was higher in the M3-HBx- and Ct-HBx-injected mice. M3-HBx had a stronger capacity of upregulating inflammatory cytokines than other HBx variants. Ectopic expression of M3-HBx and Ct-HBx significantly increased proliferation and S phase proportion of HepG2 and HeLa cells, compared to WT-HBx. Plasminogen activator inhibitor-1 (PAI1) and cell division cycle 20 (CDC20) were identified as novel effectors by cDNA microarray analysis. M3-HBx and Ct-HBx significantly upregulated the expression of PAI1 and CDC20 in HepG2 and HeLa cells as well as the livers of mice. Silencing PAI1 attenuated the effects of M3-HBx and Ct-HBx on the growth of HepG2 and HeLa cells. PAI1, an important player bridging the HBx mutants and HCC, should be a promising candidate as a prognostic biomarker and therapeutic target in HBV-related HCC.
我们旨在阐明乙型肝炎病毒X（HBx）突变增加肝细胞癌（HCC）发生的机制，并确定新的潜在治疗靶点。将野生型HBx（WT-HBx）和四种HBx突变体（M1，A1762T/G1764A；M2，T1674G+T1753C+A1762T/G1764A；M3，C1653T+T1674G+A1762T/G1764A；以及Ct-HBx，羧基末端截短的HBx）导入（）小鼠模型。在注射M3-HBx和Ct-HBx的小鼠中，HCC发病率更高。与其他HBx变体相比，M3-HBx上调炎性细胞因子的能力更强。与WT-HBx相比，M3-HBx和Ct-HBx的异位表达显著增加了HepG2和HeLa细胞的增殖及S期比例。通过cDNA微阵列分析，纤溶酶原激活物抑制剂-1（PAI1）和细胞分裂周期20（CDC20）被确定为新的效应分子。M3-HBx和Ct-HBx显著上调了HepG2和HeLa细胞以及小鼠肝脏中PAI1和CDC20的表达。沉默PAI1可减弱M3-HBx和Ct-HBx对HepG2和HeLa细胞生长的影响。PAI1是连接HBx突变体与HCC的重要因子，应是HBV相关HCC中一个有前景的预后生物标志物和治疗靶点候选物。
