E-cadherin gene mutations in human gastric carcinomacell lines.

Abstract

Reduced expression of E-cadherin has been regarded as one of the main molecular events involved in dysfunction of the cell-cell adhesion system, triggering cancer invasion and metastasis. However, even with a sufficient amount of E-cadherin, cell-cell adhesion is sometimes lost in "diffusely invasive" human carcinomas. Ten human cancer cell lines, showing growth characterized morphologically by loose cell-cell adhesion, were analyzed for possible structural abnormalities of their expressed E-cadherin. Four of the cell lines showed strong mRNA and protein expression with no nudeotide sequence abnormalities, and mRNA was absent in four other cell lines. mRNA sequence was abnormal in the remaining two gastric carcinoma cell lines. In MKN45 (poorly differentiated adenocarcinoma), this involved a 12-bp in-frame deletion with strong expression of mRNA and protein. In KATO-HI (signet ring cell carcinoma), there were four mRNA species with insertions of different sizes, among which the major transcripts (with a 7-bp insertion) caused a frameshift, and expression of both mRNA and protein was markediy reduced. In these two cell lines, DNA mutations were detected around exon-intron junctions, revealing that aberrant RNA splicing was the cause ofthe mRNA abnormalities. In addition, the wild-type allele of the E-cadherin locus was lost, suesting that the E-cadherin gene had been inactivated by two hits (mutation and allele loss), similar to the mechanism for inactivation of tumor suppressor genes.Elucidation of the molecular events involved in cancer invasion and metastasis, which determine the clinical prognosis of cancer patients, is of the utmost importance in cancer research. These phenomena should be triggered by the dissociation of cancer cells from the primary tumor through breakdown of the cell-cell adhesion system, of which one of the main component molecules is E-cadherin (for review, see ref.

Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer

“…10 Somatic E-cadherin mutations that impair the adhesive function of the protein have been described in diffuse type gastric carcinomas. [11][12][13][14][15][16] The predominant type of mutations in gastric cancer were splice-site mutations and in-frame deletions and most of the mutations were located in exons 8 or 9. 16,17 Although a number of in vitro investigations have established the significance of Rac1, IQGAP1 and Tiam1 as regulators of E-cadherin-mediated cell adhesion, little is known about the relevance of these markers in gastric cancer.…”

Promoter methylation and protein expression of the E-cadherin gene in the clinicopathologic assessment of adenoid cystic carcinoma

“…8 Abnormal E-cad expressions, including cytoplasmic translocation, heterogeneous, and/or absence of expression have been reported in aggressive carcinomas of the esophagus, stomach, and breast. 9,10 Mutation of the E-cad gene and loss of heterozygosity (LOH) of this gene have also been detected in cell lines of gastric [11][12][13][14][15] and breast carcinomas. 16 Previous studies of this gene in adenoid cystic carcinoma have reported a reduced expression of E-cad protein in high grade and aggressive tumors.…”

E-cadherin in canine mast cell tumors: Decreased expression and altered subcellular localization in Grade 3 tumors

“…The mechanisms that lead to the loss of E-cadherin expression in the cell membrane are still unclear. The disruption of cell-to-cell adhesion might be mediated by several factors, such as digestion by proteases (Lochter et al, 1997;Steinhusen et al, 2001), transcriptional repression (Batlle et al, 2000;Cano et al, 2000;Yap et al, 2007), endocytosis (Fujita et al, 2002), mutations in the E-cadherin gene (Oda et al, 1994;Saito et al, 2001) and methylation of E-cadherin promoter (Yoshiura et al, 1995).…”