Abstract
BackgroundThe importance of 17β-estradiol (E2) in the prevention of large bowel tumorigenesis has been shown in many epidemiological studies. Extragonadal E2 may form by the aromatase pathway from androstenedione or the sulfatase pathway from estrone (E1) sulfate followed by E1 reduction to E2 by 17-β-hydroxysteroid dehydrogenase (HSD17B1), so HSD17B1 gene expression may play an important role in the production of E2 in peripheral tissue, including the colon.MethodsHSD17B1 expression was analyzed in colorectal cancer cell lines (HT29, SW707) and primary colonic adenocarcinoma tissues collected from fifty two patients who underwent radical colon surgical resection. Histopathologically unchanged colonic mucosa located at least 10-20 cm away from the cancerous lesions was obtained from the same patients. Expression level of HSD17B1 using quantitative PCR and western blot were evaluated. DNA methylation level in the 5' flanking region of HSD17B1 CpG rich region was assessed using bisulfite DNA sequencing and HRM analysis. The influence of DNA methylation on HSD17B1 expression was further evaluated by ChIP analysis in HT29 and SW707 cell lines. The conversion of estrone (E1) in to E2 was determined by electrochemiluminescence method.ResultsWe found a significant decrease in HSD17B1 transcript (p = 0.0016) and protein (p = 0.0028) levels in colorectal cancer (CRC) from the proximal but not distal colon and rectum. This reduced HSD17B1 expression was associated with significantly increased DNA methylation (p = 0.003) in the CpG rich region located in the 5' flanking sequence of the HSD17B1 gene in CRC in the proximal but not distal colon and rectum. We also showed that 5-dAzaC induced demethylation of the 5' flanking region of HSD17B1, leading to increased occupation of the promoter by Polymerase II, and increased transcript and protein levels in HT29 and SW707 CRC cells, which contributed to the increase in E2 formation.ConclusionsOur results showed that reduced HSD17B1 expression can be associated with DNA methylation in the 5' flanking region of HSD17B1 in CRC from the proximal colon.
Highlights
The importance of 17b-estradiol (E2) in the prevention of large bowel tumorigenesis has been shown in many epidemiological studies
We found significantly lower levels of HSD17B1 transcript (p = 0.0016) and protein (p = 0.0028) in primary cancerous tissues than in histopathologically unchanged tissues in patients with Colorectal cancer (CRC) in the proximal colon (Figure 1A,B,C and Table 1)
We observed a moderate correlation between mRNA and protein in cancerous (p = 0.0502) and histopathologically unchanged tissue (p = 0.0722) in the proximal colon
Summary
The importance of 17b-estradiol (E2) in the prevention of large bowel tumorigenesis has been shown in many epidemiological studies. Extragonadal E2 may form by the aromatase pathway from androstenedione or the sulfatase pathway from estrone (E1) sulfate followed by E1 reduction to E2 by 17-bhydroxysteroid dehydrogenase (HSD17B1), so HSD17B1 gene expression may play an important role in the production of E2 in peripheral tissue, including the colon. Extragonadal E2 can be formed by the aromatase pathway from the androstenedione or the sulfatase pathway from estrone (E1) sulfate, followed by E1 reduction to E2 by 17-bhydroxysteroid dehydrogenase (HSD17B1) [8,9]. It has been shown that, to genetic mutations, hypermethylation or hypomethylation of gene promoters may change the expression of cancer related genes in different malignancies, including CRC [14]. DNA methylation is carried out by DNA methyltransferases (DNMTs), and increased levels of some DNMTs account for transcriptional silencing of cancer protective genes [15]
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