CpG hypermethylation of collagen type I α 2 contributes to proliferation and migration activity of human bladder cancer

Published May 9, 2009International journal of oncology

Increased DNA methylation of a collagen gene is linked to faster growth and spread of human bladder cancer cells

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Abstract

The collagen type 1 alpha 2 (COL1A2) gene was the most up-regulated among 30,144 genes screened in bladder cancer.

COL1A2 gene inactivation through CpG methylation is associated with increased proliferation and migration activity in bladder cancer.
After treatment with 5-aza-dC, COL1A2 mRNA levels markedly increased in a bladder cancer cell line.
Cell proliferation assays showed significant growth inhibition in the COL1A2 transfectant compared to control cells (p<0.0001).
Wound healing assays indicated significant wound healing inhibition in the COL1A2 transfectant compared to wild-type cells (p=0.0016).
Promoter hypermethylation of COL1A2 was frequently observed in clinical bladder cancer specimens, with a significantly higher methylation index in cancerous tissues compared to normal epithelium (p=0.0011).
COL1A2 mRNA transcript levels were significantly lower in bladder cancer specimens than in normal bladder epithelium (p=0.0052).

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In our microarray screening of methylated genes in bladder cancer (BC), the collagen type 1 alpha 2 (COL1A2) gene was the most up-regulated among the 30,144 genes screened. We hypothesize that inactivation of the COL1A2 gene through CpG methylation contributes to proliferation and migration activity of human BC. We subjected a bladder cancer cell line (BOY) and 67 BC specimens and 10 normal bladder epitheliums (NBEs) to conventional or real-time methylation quantitative polymerase chain reaction (PCR) and to real-time reverse transcriptase (RT)-PCR. We also established a stable COL1A2 transfectant for evaluating cell proliferation and migration activity. After 5-aza-dC treatment, the expression levels of COL1A2 mRNA transcript markedly increased in BOY. Our cell proliferation assays consistently demonstrated growth inhibition in the COL1A2 transfectant compared with control and wild-type BOY cells (p<0.0001). Wound healing assays also showed significant wound healing inhibition in the COL1A2 transfectant compared to the counterparts (p=0.0016). We demonstrated by bisulfite DNA sequencing that the promoter hypermethylation of COL1A2 was a frequent event in clinical BCs. The methylation index of COL1A2 was significantly higher in the 67 BCs than in the 10 NBEs (p=0.0011). Conversely, COL1A2 mRNA transcript was significantly lower in the BCs than in the NBEs (p=0.0052). The mechanism of COL1A2 down-regulation in BC is through CpG hypermethylation of the promoter region. COL1A2 gene inactivation through CpG hypermethylation may contribute to proliferation and migration activity of BC.

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CpG hypermethylation of collagen type I α 2 contributes to proliferation and migration activity of human bladder cancer

Abstract

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