EVI 1 , a target gene for amplification at 3q26, antagonizes transforming growth factor‐β‐mediated growth inhibition in hepatocellular carcinoma

EVI 1 (ecotropic viral integration site 1) is one of the most aggressive oncogenes associated with myeloid leukemia. We investigated DNA copy number aberrations in human hepatocellular carcinoma ( HCC ) cell lines using a high‐density oligonucleotide microarray. We found that a novel amplification a...

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Bibliographic Details
Published in:Cancer science 2015-07, Vol.106 (7), p.929-937
Main Authors: Yasui, Kohichiroh, Konishi, Chika, Gen, Yasuyuki, Endo, Mio, Dohi, Osamu, Tomie, Akira, Kitaichi, Tomoko, Yamada, Nobuhisa, Iwai, Naoto, Nishikawa, Taichiro, Yamaguchi, Kanji, Moriguchi, Michihisa, Sumida, Yoshio, Mitsuyoshi, Hironori, Tanaka, Shinji, Arii, Shigeki, Itoh, Yoshito
Format: Article
Language:English
Subjects:
Artificial chromosomes
Cell cycle
Cell growth
Cell viability
Chromosome 3
Copy number
Cyclin D1
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA microarrays
Enzyme inhibitors
Gene amplification
Gene therapy
Genomes
Growth factors
Hepatitis
Hepatocellular carcinoma
Kinases
Leukemia
Liver cancer
Mutation
Myc protein
Myeloid leukemia
Oligonucleotides
Pathogenesis
Phosphorylation
Prothrombin
Transcription
Transforming growth factor-b
Tumor cell lines
Tumor markers
Tumors
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Summary:EVI 1 (ecotropic viral integration site 1) is one of the most aggressive oncogenes associated with myeloid leukemia. We investigated DNA copy number aberrations in human hepatocellular carcinoma ( HCC ) cell lines using a high‐density oligonucleotide microarray. We found that a novel amplification at the chromosomal region 3q26 occurs in the HCC cell line JHH ‐1, and that MECOM ( MDS 1 and EVI 1 complex locus), which lies within the 3q26 region, was amplified. Quantitative PCR analysis of the three transcripts transcribed from MECOM indicated that only EVI 1 , but not the fusion transcript MDS 1– EVI 1 or MDS 1 , was overexpressed in JHH ‐1 cells and was significantly upregulated in 22 (61%) of 36 primary HCC tumors when compared with their non‐tumorous counterparts. A copy number gain of EVI 1 was observed in 24 (36%) of 66 primary HCC tumors. High EVI 1 expression was significantly associated with larger tumor size and higher level of des‐γ‐carboxy prothrombin, a tumor marker for HCC . Knockdown of EVI 1 resulted in increased induction of the cyclin‐dependent kinase inhibitor p15 INK 4B by transforming growth factor ( TGF )‐β and decreased expression of c‐Myc, cyclin D1, and phosphorylated Rb in TGF ‐β‐treated cells. Consequently, knockdown of EVI 1 led to reduced DNA synthesis and cell viability. Collectively, our results suggest that EVI 1 is a probable target gene that acts as a driving force for the amplification at 3q26 in HCC and that the oncoprotein EVI 1 antagonizes TGF ‐β‐mediated growth inhibition of HCC cells.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.12694