EVI1, a target gene for amplification at 3q26, antagonizes transforming growth factor‐β‐mediated growth inhibition in hepatocellular carcinoma

Abstract

EVI1 (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 (MDS1 and EVI1 complex locus), which lies within the 3q26 region, was amplified. 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 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 EVI1 was observed in 24 (36%) of 66 primary HCC tumors. High EVI1 expression was significantly associated with larger tumor size and higher level of des-γ-carboxy prothrombin, a tumor marker for HCC. Knockdown of EVI1 resulted in increased induction of the cyclin-dependent kinase inhibitor p15INK4B 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 EVI1 led to reduced DNA synthesis and cell viability. 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 antagonizes TGF-β-mediated growth inhibition of HCC cells.

Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile

“…Among genes enriched in those pathways, some have been confirmed to be closely associated with HCC. For examples, fos and mecom , which are oncogenes involved in proliferation and differentiation, have been reported to promote HCC when overexpressed5253; pparg , which was down-regulated in DEN and up-regulated in DEN+DR (data not shown), is a gene responsible for coding protein PPARγ that has been proved to protect aginst hepatocellular carcinoma by inhibiting cell growth, migration, invasion, metastasis and inducing apoptosis both in vitro and in vivo studies545556. Furthmore, Yu et al .…”

Overexpression of ecotropic viral integration site-1 is a prognostic factor of lung squamous cell cancer

“…Many previous studies have proved the oncogenic role of EVI1 in tumors, especially tumors of hematopoietic system 17. More and more emerging evidence has indicated the oncogenic role of EVI1 in solid tumors, including prostate cancer, ovarian cancer, glioblastoma, hepatocellular carcinoma, and so on 7,9,18. The underlying molecular mechanism of how EVI1 promotes cancer progression and affects prognosis has not been well elucidated.…”

“…The underlying molecular mechanism of how EVI1 promotes cancer progression and affects prognosis has not been well elucidated. Yasui et al proved that EVI1 could antagonize transforming growth factor-β-mediated growth inhibition in hepatocellular carcinoma, which promotes the proliferation of hepatocellular carcinoma cells 18. However, some sporadic studies pointed out the dual role of EVI1 in cancer progression.…”

Recent updates of genetic and genomic alterations in hepatocellular carcinoma

“…EVI1 antagonizes TGF-β-mediated growth inhibition in HCC cells, suggesting the EVI1 may be a potential molecular target for the development of novel therapies to treat HCC. [34] In another study, granulin-epithelin precursor, a secretory growth factor, was identified with gene amplification in 20% of HCC cases, and this amplification was correlated with enhanced expression levels in the same HCC cases. [35] Human epithelial growth factor receptor-2 (HER2) and topoisomerase II alpha (TOP2A) have been identified to be co-amplified in breast and some other cancers, [36] but the HER2 gene status and HER2 protein expression in HCC has been controversial.…”

“…Recently, researchers found amplification of the ecotropic viral integration site 1 (EVI1) gene at the chromosomal region 3q26 in the HCC cell line JHH-1. [34] A copy number gain of EVI1 was observed in 36% (24/66) of primary HCC tumors. EVI1 antagonizes TGF-β-mediated growth inhibition in HCC cells, suggesting the EVI1 may be a potential molecular target for the development of novel therapies to treat HCC.…”