C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism

Zhang，Yu1,2; Yan，Qian3,4; Gong，Lanqi1,2; Xu，Hang5; Liu，Beilei1,2; Fang，Xiaona1,2; Yu，Dandan1,2,6; Li，Lei1,2; Wei，Ting7; Wang，Ying1,2; Wong，Ching Ngar1,2; Lyu，Zhaojie1,2; Tang，Ying1,2; Sham，Pak Chung5; Guan，Xin Yuan1,2,4,8

2020

10.1038/s41388-020-01593-5

ONCOGENE   影响因子和分区

0950-9232

1476-5594

Chronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integration breakpoints in HBV-positive HCC samples revealed the preferential clustering pattern within the 3′-end of X gene in the HBV genome, leading to the production of C-terminal truncated X protein (Ct-HBx). In this study, we not only characterized the oncogenic role of two Ct-HBx (HBx-120 and HBx-134) via in vitro and in vivo functional assays but also deciphered their underlying molecular mechanisms. Gene expression profiling by transcriptome sequencing identified potential targets of Ct-HBx and novel malignant hallmarks such as glycolysis, cell cycle, and m-TORC1 signaling in Ct-HBx-expressing cells. TXNIP, a well-established regulator of glucose metabolism, was shown to be downregulated by Ct-HBx and play a pivotal role in Ct-HBx-mediated HCC progression. Suppression of TXNIP is frequently observed in HCC patients with Ct-HBx expression and significantly (P = 0.015) correlated to a poorer prognosis. Re-introduction of TXNIP attenuated the metabolic reprogramming induced by the Ct-HBx and inhibited the tumor growth in the mice model. Further study suggested that Ct-HBx could downregulate TXNIP via a transcriptional repressor nuclear factor of activated T cells 2 (NFACT2). Collectively, our findings indicate that TXNIP plays a critical role in Ct-HBx-mediated hepatocarcinogenesis, serving as a novel therapeutic strategy in HCC treatment.

SCI

英语

其他

Hong Kong Research Grant Council (RGC)[C7065-18GF][C7026-18GF][T12-704/16-R] ; Research Grant Council (RGC)[17143716] ; National Key R&D Program of China[2017YFC1309000] ; National Natural Science Foundation of China[81903049][81772554] ; Shenzhen Peacock Team Project[KQTD201533117210153][KQTD2018041118502879]

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

WOS:000599126500007

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85097529675

Scopus

1.Department of Clinical Oncology,The University of Hong Kong,Hong Kong
2.State Key Laboratory for Liver Research,The University of Hong Kong,Hong Kong
3.Research Center of Medical Science,Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences,Guangzhou,510030,China
4.Department of Clinical Oncology,The University of Hong Kong-Shenzhen Hospital,Shenzhen,518053,China
5.Department of Psychiatry,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong
6.Department of Biology,The Southern University of Science and Technology,Shenzhen,518055,China
7.Department of Oncology,Zhujiang Hospital,Southern Medical University,Guangzhou,510282,China
8.State Key Laboratory of Oncology in Southern China,Sun Yat-sen University Cancer Center,Guangzhou,510060,China

Zhang，Yu,Yan，Qian,Gong，Lanqi,et al. C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism[J]. ONCOGENE,2020,40(6).

Zhang，Yu.,Yan，Qian.,Gong，Lanqi.,Xu，Hang.,Liu，Beilei.,...&Guan，Xin Yuan.(2020).C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism.ONCOGENE,40(6).

Zhang，Yu,et al."C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism".ONCOGENE 40.6(2020).