Open AccessEVI 1 , a target gene for amplification at 3q26, antagonizes transforming growth factor‐β‐mediated growth inhibition in hepatocellular carcinoma
Author(s) -
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
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12694
Subject(s) - gene knockdown , biology , cancer research , cyclin d1 , microbiology and biotechnology , transforming growth factor , cell growth , hepatocellular carcinoma , cell culture , cell , cell cycle , genetics
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.