Abstract
Hepatocyte growth factor (HGF) expression is a poor prognostic factor in various types of cancer. Expression levels of HGF have been reported to be regulated by shorter poly(dA) sequences in the promoter region. In the present study, the poly(dA) mononucleotide tract in various types of human cancer cell lines was examined and compared with the HGF expression levels in those cells. Short deoxyadenosine repeat sequences were detected in five of the 55 cell lines used in the present study. The H69, IM95, CCK-81, Sui73 and H28 cells exhibited a truncated poly(dA) sequence in which the number of poly(dA) repeats was reduced by ≥5 bp. Two of the cell lines exhibited high HGF expression, determined by reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The CCK-81, Sui73 and H28 cells with shorter poly(dA) sequences exhibited low HGF expression. The cause of the suppression of HGF expression in the CCK-81, Sui73 and H28 cells was clarified by two approaches, suppression by methylation and single nucleotide polymorphisms in the HGF gene. Exposure to 5-Aza-dC, an inhibitor of DNA methyltransferase 1, induced an increased expression of HGF in the CCK-81 cells, but not in the other cells. Single-nucleotide polymorphism (SNP) rs72525097 in intron 1 was detected in the Sui73 and H28 cells. Taken together, it was found that the defect of poly(dA) in the HGF promoter was present in various types of cancer, including lung, stomach, colorectal, pancreas and mesothelioma. The present study proposes the negative regulation mechanisms by methylation and SNP in intron 1 of HGF for HGF expression in cancer cells with short poly(dA).
Highlights
Hepatocyte growth factor (HGF) is a widely‐expressed multifunctional growth and angiogenic factor [1]
The +247T Single‐nucleotide polymorphism (SNP) in intron 1 was detected in only the Sui73 and H28 cells with a short poly(dA). These results suggest that insertion of a single T nucleotide at position 247 may be associated with the expression of HGF in the Sui73 and H28 cells with a short poly(dA)
The deletion mutation on the HGF promoter region was detected in lung, colon, stomach, pancreatic and mesothelial cancer cell lines
Summary
Hepatocyte growth factor (HGF) is a widely‐expressed multifunctional growth and angiogenic factor [1]. The HGF level is frequently increased in advanced cancer patients. HGF is reported to be associated with resistance to molecular target drugs, including EGFR‐specific tyrosine kinase inhibitors, in lung cancer [6,7]. The HGF gene promoter in humans and mice has been structurally and functionally analyzed [8,9,10]. Inflammatory cytokines, including interleukin‐1- and interleukin‐6‐responsive elements, are present in the human HGF gene [8], which is activated transcriptionally by these cytokines. Ma et al reported that high expression of HGF is regulated by a short deletion in the poly(dA) repeat sequence in the HGF promoter region in breast cancer cells [11]. The present study investigated the association between the expression levels of HGF in those cells and additional regulation mechanisms of HGF expression
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