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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.

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: liuhuigg@hotmail.com.
9
The Department of Medical Genetics, Second Military Medical University, Shanghai, China. Electronic address: yangfusq1997@smmu.edu.cn.
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: ehphwp@126.com.

Abstract

BACKGROUND & AIMS:

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 impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact.

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 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival 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 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails 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 is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC.

LAY SUMMARY:

We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.

KEYWORDS:

BCLC staging; Cell proliferation; Genotype; HBx; Prognosis

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

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