Grant-in-Aid for Scientific Research (A)
|Research Institution||National Cancer Center Research Institute|
HIROHASHI Setsuo National Cancer Center Research Institute, Director, 副所長 (70129625)
KANAI Yae National Cancer Center Reaearch Institute East, Section Head, 病理部, 室長 (00260315)
SAKAMOTO Michiie National Cancer Center Reaearch Institute East, Section Head, 病理部, 室長 (40221270)
YAMADA Tesshi National Cancer Center Reaearch Institute East, Section Head, 病理部, 室長 (30221659)
OCHIAI Atsushi National Cancer Center Reaearch Institute East, Division Chief, 支所, 部長 (60183034)
野口 雅之 国立がんセンター研究所, 病理部, 室長 (00198582)
TSUDA Hitoshi National Cancer Center Reaearch Institute East, Section Head, 病理部, 室長 (70217321)
|Project Fiscal Year
1995 – 1998
Completed(Fiscal Year 1998)
|Budget Amount *help
¥36,300,000 (Direct Cost : ¥36,300,000)
Fiscal Year 1998 : ¥5,600,000 (Direct Cost : ¥5,600,000)
Fiscal Year 1997 : ¥4,600,000 (Direct Cost : ¥4,600,000)
Fiscal Year 1996 : ¥6,900,000 (Direct Cost : ¥6,900,000)
Fiscal Year 1995 : ¥19,200,000 (Direct Cost : ¥19,200,000)
|Keywords||cell adhesion / invasion and metastasis / cadherin / catenin / integrin / tyrosine phosphorylation / c-erbB-2 / signal transduction / 細胞接着 / 浸潤・転移 / カドヘリン / カテニン / インテグリン / チロシンリン酸化 / シグナル伝達 / がん間質相互作用 / 多段階発がん / カドヘリン・カテニン / DNAメチル化|
The cadherin system which mediates CaィイD12+ィエD1ependent hemophilic cell-cell adhesion, acts as an "invasion suppressor" and this system is inactivated by multiple mechanisms in carcinoma cells.
Mutations have been found in the genes for E-cadherin, a major cadherin in epithelial cells, and its undercoat proteins, α- and β- catenins, which connect E-cadherin to actin filaments and establish firm cell-cell adhesion.
Transcriptional inactivation of E-cadherin expression was also shown to play a significant role. We demonstrated CpG methylation around the promoter region of the E-cadherin gene and induction of E-cadherin expression following treatment with the DNA methyltransferase inhibitor 5-azacytidine in human cancer cell lines lacking E-cadherin expression, suggesting that E-cadherin expression in human cancer cells is regulated by CpG methylation around the promoter region. In vivo, CpG methylation around the promoter region of the E-cadherin gene significantly correlates with reduced
E-cadherin expression, resulting in loss of intercellular adhesiveness and destruction of tissue structure in hepatocellular carcinomas.
Another process contributing to the disruption of cadherin function is the aberrant tyrosine phosphorylation of the members of cadherin-catenin complex, especially β-catenin. We looked for kinases which participate in the aberrant tyrosine phosphorylation and found that the c-erbB-2 gene product directly associates with β-catenin.
This observation is the first evidence indicating the interaction between oncogene products and cell-cell adhesion molecules.
Transfection of N-terminally deleted β-catenin, which binds to c-erbB-2 but not to cadherin, inhibited the association between endogenous β-catenin and c-erbB-2 protein, and suppressed the tyrosine phosphorylation of β-catenin in gastrointestinal cancer cells. Cells expressing truncated β-catenin exhibited markedly reduced invasiveness and metastatic ability, and developed an epithelial morphology. Regulation of the system by tyrosine phosphorylation of β-catenin may be of importance in signal transduction pathways contributing to the determination of biological properties of human cancers.
In N-terminally deleted p-catenin transfectants, integrin ΒィイD24ィエD2 expression was increased. Based on this finding, we also focused on the crosstalk between the cadherin and integrin systems. Phorbol ester treatment induced formation of focal adhesion and rapid spreading of cancer cells through tyrosine phosphorylation of paxillin, an undercoat protein of integrins, and disappearance of E-cadherin and β-catenin from cell membrane. In vivo and in vitro models for urinary bladder carcinomas indicated that integrin ΒィイD24ィエD2 plays a role in intraepithelial spreading of carcinoma in situ through enhanced migration of cancer cells on laminin. Mechanism regulating ΒィイD24ィエD2 expression was also studied. Less