一种新的HBx基因型可作为术前预测因子，不能激活肝细胞癌

StephenW

J Hepatol. 2019 Jan 14. pii: S0168-8278(19)30018-2. doi: 10.1016/j.jhep.2019.01.007. [Epub ahead of print]
A novel HBx genotype serves as a preoperative predictor and fails to activate the JAK1/STATs pathway in hepatocellular carcinoma.
Xu QG1, Yuan SX2, Tao QF2, Yu J2, Cai J2, Yang Y2, Guo XG2, Lin KY3, Ma JZ4, Dai DS2, Wang ZG2, Gu FM2, Zhao LH2, Li LQ5, Liu JF6, Sun SH4, Zang YJ7, Liu H8, Yang F9, Zhou WP10.
Author information

1
    The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China; Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China.
2
    The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
3
    The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China; Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian, China.
4
    The Department of Medical Genetics, Second Military Medical University, Shanghai, China.
5
    Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China.
6
    Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian, China.
7
    Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China.
8
    The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China. Electronic address: [email protected].
9
    The Department of Medical Genetics, Second Military Medical University, Shanghai, China. Electronic address: [email protected].
10
    The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China. Electronic address: [email protected].

Abstract
BACKGROUND:

Genetic variability in the Hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impacts of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear.
METHODS:

We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n=284). Two independent HBV-related HCC cohorts, a validation cohort (n=171) and a serum cohort (n=168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism.
RESULTS:

In the primary cohort, the HBx DNA was classified into three genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival (RFS) and overall survival (OS) for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 lost its proliferation-promoting function in HCC cells and normal hepatocytes and failed to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway.
CONCLUSION:

Our study identifies a novel HBx genotype that results in a loss of proliferation promotion function and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B HBV-related HCC.
LAY SUMMARY:

A novel HBx genotype, HBx-E2, was identified in tumor and nontumor tissues from patients with HBV-related HCC and HBx-E2 could preoperatively predict the prognosis of patients with BCLC stage B HCC after resection.

Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
KEYWORDS:

BCLC staging; Cell proliferation; Genotype; HBx; Prognosis

PMID:
    30654066
DOI:
    10.1016/j.jhep.2019.01.007

StephenW

J Hepatol。 2019年1月14日.pii：S0168-8278（19）30018-2。 doi：10.1016 / j.jhep.2019.01.007。 [提前打印]
一种新的HBx基因型可作为术前预测因子，不能激活肝细胞癌中的JAK1 / STATs通路。
Xu QG1，Yuan SX2，Tao QF2，Yu J2，Cai J2，Yang Y2，Guo XG2，Lin KY3，Ma JZ4，Dai DS2，Wang ZG2，Gu FM2，Zhao LH2，Li LQ5，Liu JF6，Sun SH4，Zang YJ7 ，刘H8，杨F9，周WP10。
作者信息

1
    上海市东方肝胆外科医院第三肝外科，上海;青岛大学附属医院器官移植中心，青岛，中国。
2
    上海市东方肝胆外科医院第三肝外科，上海
3
    上海市东方肝胆外科医院第三肝外科，上海;福建医科大学孟超肝胆外科医院，福建。
4
    第二军医大学医学遗传学系，上海。
五
    广西医科大学附属肿瘤医院肝胆外科，广西
6
    福建医科大学孟超肝胆外科医院，福建。
7
    青岛大学附属医院器官移植中心，青岛，中国。
8
    上海市东方肝胆外科医院第三肝外科，上海电子地址：[email protected]。
9
    第二军医大学医学遗传学系，上海。电子地址：[email protected]。
10
    上海市东方肝胆外科医院第三肝外科，上海;中国教育部肝病信号调控与靶向治疗重点实验室（SMMU）;上海市肝胆肿瘤生物学重点实验室（EHBH），上海。电子地址：[email protected]。

抽象
背景：

经常观察到乙型肝炎病毒X基因（HBx）的遗传变异并且与肝细胞癌（HCC）进展相关。然而，基于全长HBx序列的基因型分类和基因型对乙型肝炎病毒（HBV）相关的HCC预后的影响仍不清楚。
方法：

我们对全长HBx基因的基因型进行了分类，并对来自HBV相关HCC患者队列的HBx DNA进行了聚类分析，该患者作为主要队列（n = 284）。两个独立的HBV相关HCC队列，验证队列（n = 171）和血清队列（n = 168）用于验证结果。进行蛋白质微阵列测定分析以探索潜在的机制。
结果：

在主要队列中，HBx DNA被分为三种基因型：HBx-EHBH1，HBx-EHBH2和HBx-EHBH3。 HBx-EHBH2（HBx-E2）表明HCC患者的无复发生存期（RFS）和总生存期（OS）更好。 HBx-E2与缺乏肝硬化，小肿瘤大小，孤立肿瘤，完全包裹和巴塞罗那临床肝癌（BCLC）A-0期肿瘤显着相关。此外，HBx-E2是肝切除术后BCLC B期HCC患者的重要预后因素。在机制上，HBx-E2在HCC细胞和正常肝细胞中失去其增殖促进功能，并且未能激活Janus激酶1（JAK1）/信号转导和转录激活因子3（STAT3）/ STAT5途径。
结论：

我们的研究确定了一种新的HBx基因型，导致增殖促进功能丧失，并提示术前预测BCLC B期HBV相关HCC患者预后的潜在标志物。
LAY概要：

在HBV相关性HCC和HBx-E2患者的肿瘤组织和非肿瘤组织中发现了一种新的HBx基因型HBx-E2，术前可预测切除后BCLC B期HCC患者的预后。

版权所有©2019欧洲肝脏研究协会。由Elsevier B.V.发布。保留所有权利。
关键词：

BCLC分期;细胞增殖;基因型; HBx蛋白;预测

结论：
    306540​​66
DOI：
    10.1016 / j.jhep.2019.01.007