Alterations of the cadherin-catenin cell adhesion system in cancers.
The E-cadherin-mediated cell adhesion system acts as an "invasion suppressor" system, which is widely considered to be inactivated when the expression of E-cadherin is reduced and/or heterogeneous. To further investigate the molecular mechanisms responsible for dysfunction of this system in cancers, we examined human carcinoma cell lines lacking tight cell-cell adhesion. In KATO-III, established from stomach cancer, a point mutation of the E-cadherin gene resulted in a mRNA splicing error and markedly reduced E-cadherin expression. In another stomach cancer cell line, MKN 45, an 18-bp deletion of the E-cadherin gene caused a mRNA splicing error and a 4-amino-acid deletion, which was considered to alter the conformation around the key Ca(2+)-binding motif. In these two cell lines, the wild-type allele of the E-cadherin locus, which was assigned to chromosome 16q, was lost. Also in vivo, we found mutation of E-cadherin in breast cancers, where allele loss on chromosome 16 has frequently been reported. Thus, dysfunction of E-cadherin could be caused by a combination of the loss of one allele and a mutation in the remaining allele. Homologous deletion of part of the alpha-catenin gene, resulting in markedly reduced expression, was observed in a human lung cancer cell line, PC9. Recently, we also found mutations of beta-catenin in human carcinoma cell lines. These findings indicate the possible involvement of genetic abnormalities of various components in inactivation of the E-cadherin-mediated "invasion suppressor system" in cancers.
Kanai
Y
Y
Pathology Division, National Cancer Center Research Institute Tokyo, Japan.
Oda
T
T
Shimoyama
Y
Y
Ochiai
A
A
Oyama
T
T
Yoshiura
K
K
Akimoto
S
S
Yamada
T
T
Hirohashi
S
S
D001665:Binding Sites; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011487:Protein Conformation; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015534:Trans-Activators; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000648:ultrastructure; D051178:alpha Catenin; D051176:beta Catenin
C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin; D002118:Calcium