TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer

Abstract

The existence of tumor-suppressor genes was originally demonstrated by functional complementation through whole-cell and microcell fusion. Transfer of chromosome 11 into a human non-small-cell lung cancer (NSCLC) cell line, A549, suppresses tumorigenicity. Loss of heterozygosity (LOH) on the long arm of chromosome 11 has been reported in NSCLC and other cancers. Several independent studies indicate that multiple tumor-suppressor genes are found in this region, including the gene PPP2R1B at 11q23-24 (ref. 7). Linkage studies of NSCLC are precluded because no hereditary forms are known. We previously identified a region of 700 kb on 11q23.2 that completely suppresses tumorigenicity of A549 human NSCLC cells. Most of this tumor-suppressor activity localizes to a 100-kb segment by functional complementation. 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. TSLC1 expression or suppression is correlated with promoter methylation state in these cell lines. Restoration of TSLC1 expression to normal or higher levels suppresses tumor formation by A549 cells in nude mice. 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. Promoter methylation was observed in 15 of the other 18 primary NSCLC, HCC and PaC tumors with LOH for 11q23.2. Thus, attenuation of TSLC1 expression occurred in 85% of primary tumors with LOH. Hypermethylation of the TSLC1 promoter would seem to represent the 'second hit' in NSCLC with LOH.

Expression of the tumour suppressor gene CADM1 is associated with favourable outcome and inhibits cell survival in neuroblastoma

“…Low endogenous CADM1 protein expression was found in three of four neuroblastoma cell lines, which corresponds well to the range of CADM1 transcript levels in patients with poor outcome (Figures 1 and 4). Different levels of endogenous CADM1 expression have been reported for several human cancer cell lines (Kuramochi et al, 2001;Ito et al, 2003b), and were considered to be a result of a complex regulatory network of important molecules, such as APC (Naishiro et al, 2005), ErbB4 (Ojeda et al, 2006) and MITF (Ito et al, 2003a). The significant protein level of endogenous CADM1 in Kelly cells might thus result from individual molecular characteristics of this cell line such as high MYCN expression.…”

“…The putative tumour suppressor gene CADM1 has been described to be inactivated in numerous solid human tumours including liver, pancreatic, breast, brain and prostate cancers (Kuramochi et al, 2001;Fukuhara et al, 2002;Jansen et al, 2002;Houshmandi et al, 2006;Heller et al, 2007), and there has been considerable interest in understanding the biological significance of CADM1 loss in tumourigenesis. Previous investigations have supported the hypothesis of CADM1 as a general tumour suppressor-mediating apoptosis (Mao et al, 2004), differentiation (Wakayama et al, 2003) and cell cycle regulation (Ito et al, 2003b).…”

“…This gene maps to chromosome 11q23.2, a region frequently deleted in tumours such as malignant melanoma (Katoh, 2003(Katoh, , 2004, lung cancer (Gomyo et al, 1999) and neuroblastoma (Mertens et al, 1997), and encodes an immunoglobulin superfamily transmembrane molecule primarily involved in epithelial cell adhesion (Murakami, 2005). Loss of CADM1 expression has been described in many malignancies, including liver, pancreatic, breast, brain and prostate cancers, particularly in those showing invasion or metastasis (Kuramochi et al, 2001;Fukuhara et al, 2002;Jansen et al, 2002;Houshmandi et al, 2006;Heller et al, 2007). Promoter hypermethylation was reported to account for downregulation of CADM1 in several human cancers (Murakami, 2005;Ehrlich et al, 2006;Kikuchi et al, 2006;Worsham et al, 2006).…”

Nectines et nectines-like

“…Necl-2 : un gène suppresseur de tumeur dans le cancer du poumon Necl-2 est fréquemment inactivée dans les carcinomes du poumon, du pancréas et du foie [36]. Cette inactivation est le résultat de la perte d'un allèle du gène et de la méthylation du promoteur de l'autre allèle.…”

Time-Course Statistical Evaluation of Intercellular Adhesion Maturation by Femtosecond Laser Impulse

“…From these reports, the coculture system is generally regarded as a reproductive model of the anatomical and functional relationship between them. The adhesion is considered to be formed by specific bonds between cell adhesion molecules known as cell adhesion molecule-1s (CADM1s) (24,(26)(27)(28), which are membranespanning glycoproteins belonging to the immunoglobulin (Ig) superfamily (29)(30)(31)(32) and function by forming a dimer on the cell membrane (33)(34)(35).…”