Disease relevance of CADM1

• A tumor suppressor gene, TSLC1/IGSF4, from chromosomal region 11q23 was identified in non-small cell lung cancer (NSCLC) by its tumor suppressor activity in nude mice [1].
• The distinct roles of TSLC1/IGSF4 in the oncogenesis of carcinomas and ATL could be due to tissue-specific differences in the downstream cascades, and is a novel concept with respect to cell adhesion in human oncogenesis [1].
• TSLC1/IGSF4 is expressed in most tissues except for peripheral blood lymphocytes, but it is inactivated in 44% of NSCLC and 30-60% of various cancers, including liver, pancreatic, and prostate cancers, especially in those with invasion or metastasis [1].
• TSLC1/IGSF4 is ectopically expressed in adult T-cell leukemia (ATL) cells, providing not only a diagnostic marker for ATL, but also a possible therapeutic target against its invasion [1].
• Here we report that this region contains a single confirmed gene, TSLC1, whose expression is reduced or absent in A549 and several other NSCLC, hepatocellular carcinoma (HCC) and pancreatic cancer (PaC) cell lines [2].

High impact information on CADM1

• TSLC1 expression or suppression is correlated with promoter methylation state in these cell lines [2].
• TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer [2].
• 2. Thus, attenuation of TSLC1 expression occurred in 85% of primary tumors with LOH [2].
• Only 2 inactivating mutations of TSLC1 were discovered in 161 tumors and tumor cell lines, both among the 20 primary tumors with LOH for 11q23 [2].
• Here, we show that upon surface immunoglobulin cross-linking followed by co-culture with activated cloned T cells, the Burkitt's lymphoma cell line BL2 is induced to mutate its IgV(H) gene [3].

Chemical compound and disease context of CADM1

• Re-expression of TSLC1 and DAL-1 was seen after treatment of lung cancer cell lines with 5-aza-2'-deoxycytidine [4].
• The tumor suppressor gene TSLC1, which we recently identified in human non-small cell lung cancer, encodes a membrane glycoprotein of the immunoglobulin superfamily [5].
• To analyse the relationship between EBV status, fludarabine-induced apoptosis, and transcription factors we studied the EBV-negative Burkitt lymphoma cell line BL2, its EBV-infected counterpart BL2.B95.8 and the EBV-transformed cell line PRI [6].
• Using BL cell line BL2 B95-8 (BL2 infected with the B95.8 strain of EBV), we addressed the relation between EBV genome expression and modulation of viral oncoproteins by Cidofovir and/or ionizing radiation (IR) [7].
• Bisulfite sequence analysis of four lung adenocarcinomas and two normal lung tissues revealed that the 5' upstream region of the Tslc1 gene was highly methylated in the four lung adenocarcinomas, but unmethylated in the two normal lung tissues [8].

Biological context of CADM1

• Silencing of the IGSF4 gene was primarily achieved by allelic loss and promoter methylation in this type of cancers [9].
• Involvement of a cell adhesion molecule, TSLC1/IGSF4, in human oncogenesis [1].
• Tumor suppressor of lung cancer 1 (TSLC1), also known as SgIGSF, IGSF4, and SynCAM, is strongly expressed in spermatogenic cells undergoing the early and late phases of spermatogenesis (spermatogonia to zygotene spermatocytes and elongating spermatids to spermiation) [10].
• CONCLUSIONS: Our data strongly suggest that IGSF4 is a TSG and that gene silencing by aberrant hypermethylation may contribute to the development of CC [11].
• Methylation maps of the IGSF4 promoter region were generated for 11 CC cell lines based upon bisulfite-genomic sequencing, using seven nested-PCR primer sets covering 97 CpG sites [11].

Anatomical context of CADM1

• Soon after this discovery, IGSF4 was found to have roles in adhesion of spermatogenic cells to Sertoli cells and mast cells to fibroblasts and termed SgIGSF [9].
• TSLC1 methylation was seen in 13 of 39 (33%) NSCLC cell lines, in one of 11 (9%) SCLC cell lines and in 100 of 268 (37%) primary NSCLCs [4].
• Furthermore, TSLC1/IGSF4 may act as a tumor antigen recognized by activated NK or CD8+ T cells [1].
• Introduction of TSLC1 into a human ATL cell line ED enhanced both self-aggregation and adhesion ability to vascular endothelial cells [12].
• Biochemical analysis has revealed that TSLC1 is an N-linked glycoprotein with a molecular mass of 75 kDa and that it forms homodimers through cis interaction within the plane of the cell membranes [13].

Associations of CADM1 with chemical compounds

• Here, we examined the methylation status of the TSLC1 gene promoter in 48 primary NSCLC tumors by bisulfite SSCP in combination with bisulfite sequencing [14].
• In each cell line the aberrant methylation was associated with loss of TSLC1 expression by RT-PCR that was reversible after treatment with the DNA methyl-transferase inhibitor 5-aza-2'- deoxycytidine [15].
• IFN-gamma also blocked IL-4-induced CD23 mRNA transcription in BL2 completely, whereas PGE2 (10(-7) M) was partially inhibitory [16].
• During the time course of the experiment the usage of the dual promoter P1/P2 shifted from the ratio 3:1 in untreated cells to the ratio of 1:5 in BL2 cells treated with DMSO for 4 h [17].
• The BL2 cell line was found to be very sensitive to fludarabine [6].

Other interactions of CADM1

• Our results suggest that methylation of TSLC1 and/or DAL-1, leading to loss of their expression, is an important event in the pathogenesis of NSCLC [4].
• TSLC1 (tumor suppressor in lung cancer-1, IGSF4) encodes a member of the immunoglobulin superfamily molecules, which is involved in cell-cell adhesion [4].
• Association of a lung tumor suppressor TSLC1 with MPP3, a human homologue of Drosophila tumor suppressor Dlg [18].
• Methylation of IGSF4 and DAPK1 is specific for HSIL and SCC, and may serve as a useful molecular biomarker [19].
• Epigenetic inactivation of TSLC1 gene in nasopharyngeal carcinoma [20].

Analytical, diagnostic and therapeutic context of CADM1

• METHODS: IGSF4 expression was detected by both RT-PCR and Northern blot analysis [11].
• Our results demonstrate the pro-apoptotic and oncosuppressive activity of TSLC1 protein, and suggest the potential of TSLC1 for gene therapy [21].
• Whereas TSLC1 was expressed in normal human leptomeninges by immunohistochemistry, TSLC1 expression was absent in 3 human malignant meningioma cell lines and markedly reduced or absent in 30% of benign meningiomas by Western blot [22].
• We developed specific anti-TSLC1 antibodies to examine TSLC1 expression in normal human leptomeninges, human meningioma cell lines, and human meningiomas of different pathological grades by Western blot (n = 10) and immunohistochemistry (n = 123) [22].
• In addition, the disease-free survival of patients with a tumor that demonstrated a high percentage of TSLC1 protein-positive cells was reported to be significantly better than that of patients with a tumor that showed a low percentage of TSLC1 protein-positive cells [23].

References