Abstract 2034: Amplification and overexpression of EVI1 suppresses growth inhibition mediated by TGF-β in hepatocellular carcinoma
Authors: Kohichiroh Yasui, Yasuyuki Gen, Osamu Dohi, Akira Tomie, Tomoko Kitaichi, Yoshito Itoh
Journal: Cancer Research (2015)

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. EVI1 (ecotropic viral integration site 1) is one of the most aggressive oncogenes associated with myeloid leukemia. The EVI1 gene codes for a zinc finger transcriptional factor that plays an important role in normal development and in oncogenesis. In humans, rearrangements of chromosome 3q26 often activate EVI1 expression in acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Importantly, high EVI1 expression is an independent negative prognostic indicator of survival in acute myeloid leukemia. The oncoprotein EVI1 has been reported to influence a number of signaling pathways. Thus, EVI1 activates the PI3K/AKT and RAS/ERK signaling pathways. Moreover, EVI1 has been reported to suppress TGF-β signaling by inhibiting Smad3. TGF-β acts as a tumor suppressor by arresting the growth of cells in the early stages of cancer. Whereas the majority of investigations have focused on the contribution of EVI1 to the pathogenesis and clinical characteristics of hematopoietic malignancies, little is known about its relevance for HCC. To identify genes potentially involved in HCC, we investigated DNA copy number aberrations in human HCC cell lines using high-resolution single nucleotide polymorphism (SNP) arrays (Affymetrix). We found that a novel amplification at the chromosomal region 3q26 occurs in a HCC cell line and that MECOM (MDS1 and EVI1 complex locus), which lies within the 3q26 region, was amplified. Amplification of DNA in certain regions of chromosomes plays a crucial role in the development and progression of human malignancies, specifically when proto-oncogenic target genes within those amplicons are overexpressed. Quantitative PCR analysis of the three transcripts transcribed from MECOM indicated that only EVI1, but not the fusion transcript MDS1-EVI1 or MDS1, was overexpressed in HCC cell lines and was significantly up-regulated in 22 (61%) of 36 primary HCC tumors when compared with their non-tumorous counterparts. A copy number gain of EVI1 was observed in 24 (36%) of 66 primary HCC tumors. Knockdown of EVI1 in HCC cells resulted in increased induction of the cyclin-dependent kinase inhibitor p15INK4B by TGF-β and decreased expression of c-Myc, cyclin D1, and phosphorylated Rb in TGF-β-treated cells. Consequently, knockdown of EVI1 led to reduced cell proliferation of HCC. Collectively, our results suggest that EVI1 is a probable target gene that acts as a driving force for the amplification at 3q26 in HCC and that the oncoprotein EVI1 suppresses TGF-β-mediated growth inhibition of HCC cells. Citation Format: Kohichiroh Yasui, Yasuyuki Gen, Osamu Dohi, Akira Tomie, Tomoko Kitaichi, Yoshito Itoh. Amplification and overexpression of EVI1 suppresses growth inhibition mediated by TGF-β in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2034. doi:10.1158/1538-7445.AM2015-2034