Loss of expression of type IV collagen α5 and α6 chains in colorectal cancer associated with the hypermethylation of their promoter region

Abstract

Type IV collagen, a major component of the basement membrane (BM), is composed of six genetically distinct α(IV) chains, α1(IV) to α6(IV). Their genes are paired on three different chromosomes in a head-to-head arrangement. The α5(IV) gene (COL4A5) and the α6(IV) gene (COL4A6) are on chromosome Xq22 and are regulated by a bidirectional promoter. Loss of the α5(IV)/α6(IV) chains in epithelial BM occur to the early stage of cancer invasion. However, the regulatory mechanism of the specific loss of the α5(IV)/α6(IV) chains during cancer cell invasion is still undetermined. In the present study, we examined the expression of the α5(IV)/α6(IV) chains and the methylation profiles of the bidirectional promoter region of COL4A5/COL4A6 in colon cancer cell lines and colorectal tumor tissues. The expression of the α5(IV)/α6(IV) chains was down-regulated in colorectal cancer, and the loss of expression of the α5(IV)/α6(IV) chains was associated with the hypermethylation of their promoter region. In conclusion, the hypermethylation of the bidirectional promoter region of COL4A5/COL4A6 is one of the events that is responsible for the loss of expression of the α5(IV)/α6(IV) chains and the remodeling of the epithelial BM during cancer cell invasion. Copyright © American Society for Investigative Pathology.