Hepatitis B virus mRNAs functionally sequester let-7a and enhance hepatocellular carcinoma.
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.
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.
Mengmeng
M
Deng
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Junwei
J
Hou
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Jun
J
Hu
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Shuo
S
Wang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Mi
M
Chen
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Lizhao
L
Chen
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Ying
Y
Ju
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Electronic address: lichangfei2006@163.com.
Changfei
C
Li
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: mengsd@im.ac.cn.
Songdong
S
Meng
D020413:3' Untranslated Regions; D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006509:Hepatitis B / Q000150:complications / Q000821:virology*; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
D020413:3' Untranslated Regions; C466422:AGO2 protein, human; D060565:Argonaute Proteins; C515370:CCR7 protein, human; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; C117307:KRAS protein, human; C489427:MYC protein, human; D035683:MicroRNAs; D011498:Protein Precursors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012367:RNA, Viral; D054400:Receptors, CCR7; C487931:mirnlet7 microRNA, human; C050807:presurface protein 2, hepatitis B surface antigen; D016283:Proto-Oncogene Proteins p21(ras)
HBV; Hepatocellular carcinoma; Let-7a