CAGE profiling of ncRNAs in hepatocellular carcinoma reveals widespread activation of retroviral LTR promoters in virus-induced tumors.
An increasing number of noncoding RNAs (ncRNAs) have been implicated in various human diseases including cancer; however, the ncRNA transcriptome of hepatocellular carcinoma (HCC) is largely unexplored. We used CAGE to map transcription start sites across various types of human and mouse HCCs with emphasis on ncRNAs distant from protein-coding genes. Here, we report that retroviral LTR promoters, expressed in healthy tissues such as testis and placenta but not liver, are widely activated in liver tumors. Despite HCC heterogeneity, a subset of LTR-derived ncRNAs were more than 10-fold up-regulated in the vast majority of samples. HCCs with a high LTR activity mostly had a viral etiology, were less differentiated, and showed higher risk of recurrence. ChIP-seq data show that MYC and MAX are associated with ncRNA deregulation. Globally, CAGE enabled us to build a mammalian promoter map for HCC, which uncovers a new layer of complexity in HCC genomics.
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan;
Kosuke
K
Hashimoto
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan;
Ana Maria
AM
Suzuki
INSERM, U1193, Paul-Brousse Hospital, Hepatobiliary Centre, 94800 Villejuif, France; Université Paris Saclay, Faculté de Médecine Le Kremlin Bicêtre, 94800 Villejuif, France;
Alexandre
A
Dos Santos
INSERM, U1193, Paul-Brousse Hospital, Hepatobiliary Centre, 94800 Villejuif, France; Université Paris Saclay, Faculté de Médecine Le Kremlin Bicêtre, 94800 Villejuif, France;
Christophe
C
Desterke
European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, 20139 Milan, Italy;
Agnese
A
Collino
European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, 20139 Milan, Italy;
Serena
S
Ghisletti
INSERM, U1193, Paul-Brousse Hospital, Hepatobiliary Centre, 94800 Villejuif, France; Université Paris Saclay, Faculté de Médecine Le Kremlin Bicêtre, 94800 Villejuif, France;
Emilie
E
Braun
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan;
Alessandro
A
Bonetti
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan;
Alexandre
A
Fort
RIKEN Center for Life Science Technologies, Division of Bio-function Dynamics Imaging, Wako, Saitama, 351-0198, Japan;
Xian-Yang
XY
Qin
VIB Center for the Biology of Disease, KU Leuven Center for Human Genetics, B-3000 Leuven, Belgium;
Enrico
E
Radaelli
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan;
Bogumil
B
Kaczkowski
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan;
Alistair R R
AR
Forrest
RIKEN Center for Life Science Technologies, Division of Bio-function Dynamics Imaging, Wako, Saitama, 351-0198, Japan;
Soichi
S
Kojima
INSERM, U1193, Paul-Brousse Hospital, Hepatobiliary Centre, 94800 Villejuif, France; Université Paris Saclay, Faculté de Médecine Le Kremlin Bicêtre, 94800 Villejuif, France;
Didier
D
Samuel
European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, 20139 Milan, Italy;
Gioacchino
G
Natoli
INSERM, U1193, Paul-Brousse Hospital, Hepatobiliary Centre, 94800 Villejuif, France; Université Paris Saclay, Faculté de Médecine Le Kremlin Bicêtre, 94800 Villejuif, France;
Marie Annick
MA
Buendia
INSERM, U1193, Paul-Brousse Hospital, Hepatobiliary Centre, 94800 Villejuif, France; Université Paris Saclay, Faculté de Médecine Le Kremlin Bicêtre, 94800 Villejuif, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Pôle de Biologie Médicale, Paul-Brousse Hospital, 94800 Villejuif, France.
Jamila
J
Faivre
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan;
Piero
P
Carninci
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D022661:RNA, Untranslated / Q000235:genetics*; D020079:Terminal Repeat Sequences; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site; D059467:Transcriptome; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D022661:RNA, Untranslated; D014157:Transcription Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4