Specific genomic and transcriptomic aberrations in tumors induced by partial hepatectomy of a chronically inflamed murine liver.
Resection of hepatocellular carcinoma (HCC) tumors by partial hepatectomy (PHx) is associated with promoting hepatocarcinogenesis. We have previously reported that PHx promotes hepatocarcinogenesis in the Mdr2-knockout (Mdr2-KO) mouse, a model for inflammation-mediated HCC. Now, to explore the molecular mechanisms underlying the tumor-promoting effect of PHx, we compared genomic and transcriptomic profiles of HCC tumors developing in the Mdr2-KO mice either spontaneously or following PHx. PHx accelerated HCC development in these mice by four months. PHx-induced tumors had major chromosomal aberrations: all were amplifications affecting multiple chromosomes. Most of these amplifications were located near the acrocentric centromeres of murine chromosomes. Four different chromosomal regions were amplified each in at least three tumors. The human orthologs of these common amplified regions are known to be amplified in HCC. All tumors of untreated mice had chromosomal aberrations, including both deletions and amplifications. Amplifications in spontaneous tumors affected fewer chromosomes and were not located preferentially at the chromosomal edges. Comparison of gene expression profiles revealed a significantly enriched expression of oncogenes, chromosomal instability markers and E2F1 targets in the post-PHx compared to spontaneous tumors. Both tumor groups shared the same frequent amplification at chromosome 18. Here, we revealed that one of the regulatory genes encoded by this amplified region, Crem, was over-expressed in the nuclei of murine and human HCC cells in vivo, and that it stimulated proliferation of human HCC cells in vitro. Our results demonstrate that PHx of a chronically inflamed liver directed tumor development to a discrete pathway characterized by amplification of specific chromosomal regions and expression of specific tumor-promoting genes. Crem is a new candidate HCC oncogene frequently amplified in this model and frequently over-expressed in human HCC.
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Ezra
E
Ella
Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Denise
D
Heim
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Evgeniy
E
Stoyanov
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Rona
R
Harari-Steinfeld
Computer Science Department, Technion-Israel Institute of Technology, Haifa, Israel.
Israel
I
Steinfeld
Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Orit
O
Pappo
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Temima Schnitzer
TS
Perlman
Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy Laboratory, Human Biology Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Natalie
N
Nachmansson
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Ludmila
L
Rivkin
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Devorah
D
Olam
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy Laboratory, Human Biology Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Rinat
R
Abramovitch
Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Henning
H
Wege
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Eithan
E
Galun
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Daniel
D
Goldenberg
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000601:surgery; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006498:Hepatectomy; D006521:Hepatitis, Chronic / Q000235:genetics* / Q000601:surgery; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D011183:Postoperative Complications / Q000235:genetics*; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D051786:Cyclic AMP Response Element Modulator; D050687:E2F1 Transcription Factor; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C493753:E2F1 protein, human