Hepatitis B virus mRNAs functionally sequester let-7a and enhance hepatocellular carcinoma

Mengmeng Deng; Junwei Hou; Jun Hu; Shuo Wang; Mi Chen; Lizhao Chen; Ying Ju; Changfei Li; Songdong Meng

doi:10.1016/j.canlet.2016.09.028

Hepatitis B virus mRNAs functionally sequester let-7a and enhance hepatocellular carcinoma

Cancer Lett. 2016 Dec 1;383(1):62-72. doi: 10.1016/j.canlet.2016.09.028. Epub 2016 Sep 29.

Authors

Mengmeng Deng¹, Junwei Hou², Jun Hu², Shuo Wang², Mi Chen², Lizhao Chen², Ying Ju², Changfei Li³, Songdong Meng⁴

Affiliations

¹ School of Life Sciences, University of Science and Technology of China, Hefei, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
³ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Electronic address: [email protected].
⁴ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. Electronic address: [email protected].

PMID: 27693636
DOI: 10.1016/j.canlet.2016.09.028

Abstract

Hepatitis B virus (HBV) infection induces hepatocarcinogenesis and malignant progression, yet global effects of the redundant viral mRNAs produced during infection are unexplored. Here, microRNA (miRNA) target prediction and whole genome expression analysis revealed that HBV pre-C/C mRNA leads to upregulation of multiple let-7a targeted genes. A let-7a complementary region from nt 86 to 108 in the HBV genome was then identified in HBV pre-C/C, pre-S, and S mRNAs. The let-7a sequestration effect by HBV mRNAs was observed under transfection and virus infection, which is dependent on the let-7a response sequence. Moreover, we found reduced AGO2 binding, as well as functional mRNA and protein de-repression of let-7a targets (e.g., c-myc, K-RAS, and CCR7), upon viral mRNA expression. Let-7a levels in the liver were significantly decreased in hepatocellular carcinoma (HCC) patients with HBV infection and were negatively correlated with intrahepatic pre-S2 mRNA levels. Finally, both in vitro and in vivo studies demonstrated that let-7a inhibition by HBV mRNAs resulted in enhanced HCC cell colony formation and tumor growth, providing evidence of the oncogenic potential of HBV mRNAs.

Keywords: HBV; Hepatocellular carcinoma; Let-7a.

MeSH terms

3' Untranslated Regions
Animals
Argonaute Proteins / metabolism
Binding Sites
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Carcinoma, Hepatocellular / virology*
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Viral*
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Expression Regulation, Viral
Hepatitis B / complications
Hepatitis B / virology*
Hepatitis B Core Antigens / genetics
Hepatitis B Core Antigens / metabolism
Hepatitis B Surface Antigens / genetics
Hepatitis B Surface Antigens / metabolism
Hepatitis B virus / genetics*
Hepatitis B virus / metabolism
Host-Pathogen Interactions
Humans
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Liver Neoplasms / virology*
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics*
MicroRNAs / metabolism
Protein Precursors / genetics
Protein Precursors / metabolism
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
RNA, Messenger / genetics*
RNA, Messenger / metabolism
RNA, Viral / genetics*
RNA, Viral / metabolism
Receptors, CCR7 / genetics
Receptors, CCR7 / metabolism
Time Factors
Transfection
Tumor Burden

Substances

3' Untranslated Regions
AGO2 protein, human
Argonaute Proteins
CCR7 protein, human
Hepatitis B Core Antigens
Hepatitis B Surface Antigens
KRAS protein, human
MYC protein, human
MicroRNAs
Protein Precursors
Proto-Oncogene Proteins c-myc
RNA, Messenger
RNA, Viral
Receptors, CCR7
mirnlet7 microRNA, human
presurface protein 2, hepatitis B surface antigen
Proto-Oncogene Proteins p21(ras)