EVI1, a target gene for amplification at 3q26, antagonizes transforming growth factor‐β‐mediated growth inhibition in hepatocellular carcinoma. Issue 7 (5th June 2015)

• Record Type: Journal Article
• 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
• Is Part Of: Cancer science. Volume 106:Issue 7(2015:Jul.)
• Page Start: 929
• Page End: 937
• Publication Date: 2015-06-05
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12694
• Languages: English
• ISSNs: 1347-9032

Abstract

<abstract abstract-type="main" id="cas12694-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <italic>EVI1</italic> (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 <italic>MECOM</italic> (<italic>MDS1</italic> and <italic>EVI1</italic> complex locus), which lies within the 3q26 region, was amplified. Quantitative PCR analysis of the three transcripts transcribed from <italic>MECOM</italic> indicated that only <italic>EVI1</italic>, but not the fusion transcript <italic>MDS1–EVI1</italic> or <italic>MDS1</italic>, 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 <italic>EVI1</italic> was observed in 24 (36%) of 66 primary HCC tumors. High <italic>EVI1</italic> expression was significantly associated with larger tumor size and higher level of des‐γ‐carboxy prothrombin, a tumor marker for HCC. Knockdown of <italic>EVI1</italic> resulted in increased induction of the cyclin‐dependent kinase inhibitor p15<sup>INK</sup><sup>4B</sup> 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 <italic>EVI1</italic> led to reduced DNA synthesis and cell viability. Collectively, our results suggest that <italic>EVI1</italic> is a probable target gene that acts as a driving force for the amplification at 3q26 in HCC and that the oncoprotein EVI1 antagonizes TGF‐β‐mediated growth inhibition of HCC cells.</p> </abstract>