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(American Journal of Pathology. 2006;168:856-865.)
© 2006 American Society for Investigative Pathology

Loss of Expression of Type IV Collagen 5 and 6 Chains in Colorectal Cancer Associated with the Hypermethylation of Their Promoter Region

Koei Ikeda^*, Ken-ichi Iyama^*, Nobuyuki Ishikawa, Hiroshi Egami, Mitsuyoshi Nakao, Yoshikazu Sado, Yoshifumi Ninomiya^¶ and Hideo Baba

From the Department of Surgical Pathology,^* Kumamoto University School of Medicine, Kumamoto; the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, and the Department of Regeneration Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto; the Division of Immunology, Shigei Medical Research Institute, Okayama; and the Department of Molecular Biology and Biochemistry,^¶ Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

Type IV collagen, a major component of the basement membrane (BM), is composed of six genetically distinct (IV) chains, 1(IV) to 6(IV). Their genes are paired on three different chromosomes in a head-to-head arrangement. The 5(IV) gene (COL4A5) and the 6(IV) gene (COL4A6) are on chromosome Xq22 and are regulated by a bidirectional promoter. Loss of the 5(IV)/6(IV) chains in epithelial BM occur in the early stage of cancer invasion. However, the regulatory mechanism of the specific loss of the 5(IV)/6(IV) chains during cancer cell invasion is still undetermined. In the present study, we examined the expression of the 5(IV)/6(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 5(IV)/6(IV) chains was down-regulated in colorectal cancer, and the loss of expression of the 5(IV)/6(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 5(IV)/6(IV) chains and the remodeling of the epithelial BM during cancer cell invasion.

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