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.