Identification of a novel phospholipase C family gene at chromosome 2q33 that is homozygously deleted in human small cell lung carcinoma

Kohno, Takashi; Otsuka, Toshiyuki; Takano, Hirokuni; Yamamoto, Tadashi; Hamaguchi, Masaaki; Terada, Masaaki; Yokota, Jun

doi:10.1093/hmg/4.4.667

Cited by 46 publications

(31 citation statements)

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“…It has been suggested that one or more other tumor suppressor genes are located within the 2q33 region and PLC-L has been suggested as a candidate. 38 In both SCLC and NSCLC cell lines, we found a 100% concordance between gene expression by RT-PCR and protein expression by Western blotting. In a subset of cell lines, gene expression of CSP8 correlated with functional activity.…”

Section: Loh Analysis Of Lung Cancer Cell Linesmentioning

confidence: 63%

Differential Inactivation of Caspase-8 in Lung Cancers

Shivapurkar¹,

Toyooka²,

Eby³

et al. 2002

Cancer Biology & Therapy

140

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© 2 0 0 2 L a n d e s is an apoptosis inducing cysteine protease which is activated through the formation of a death-inducing signaling complex when death receptors are complexed to their specific ligands. Recent reports indicate that CASP8 expression is lost via a combination of promoter methylation and allelic loss in a subset of neuroblastomas. We investigated the state of the gene in lung tumors and cell lines. RT-PCR studies indicated that gene expression was lost in most (27 of 34, 79%) of small cell lung carcinoma (SCLC) cell lines, but expression was retained in all 22 non-SCLC (NSCLC) lines tested. Loss of gene expression at the RNA level was associated with absent protein expression by Western blotting and lack of CASP8 enzymatic activity. Methylation of the promoter region of the CASP8 gene was present in 16 of 27 (59%) of the SCLC lines lacking gene expression. All methylated cell lines lacked the presence of an unmethylated allele indicating biallelic methylation or loss of non-methylated allele. Promoter methylation was absent in all SCLC and NSCLC cell lines retaining gene expression, and all of these lines had the unmethylated form of the gene. One non-expressing SCLC cell line, NCI-H82, had a homozygous deletion at 2q33 encompassing the chromosomal location of the CASP8 gene. The mechanism of gene inactivation in the remaining 10 of 27 (37%) non-expressing SCLC cell lines is unknown. Using five polymorphic markers for 2q33 a high frequency of allelic loss was present in SCLC lines. Analyses of fresh tumors showed that 15 of 43 (35%) of the SCLC, seven of 40 (18%) of bronchial carcinoids and none of 44 NSCLC tumors had CASP8 promoter methylation. Because only approximately 60% of SCLC cell lines lacking CASP8 expression were methylated, extrapolating from the cell line data, we estimate that approximately 58% of SCLC and 30% of bronchial carcinoids lack CASP8 expression. Thus, CASP8 expression is absent in a subset of both high grade (SCLC) and low grade (carcinoid) neuroendocrine lung tumors but not in NSCLC, which usually lack neuroendocrine features. CASP8 may function as a tumor suppressor gene in neuroendocrine lung tumors. B i o s c i e n c e . N o t f o r d i s t r i b u t i o n .

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Section: Loh Analysis Of Lung Cancer Cell Linesmentioning

confidence: 63%

Differential Inactivation of Caspase-8 in Lung Cancers

Shivapurkar¹,

Toyooka²,

Eby³

et al. 2002

Cancer Biology & Therapy

140

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“…On the 2q33 band, frequent LOH was also revealed in various human tumors, including neuroblastoma and lung cancer. In this locus, the caspase 8 gene for neuroblastoma (Takita et al, 2001), TPEF for various tumor cell lines, and the PLC-L gene for small cell lung carcinoma (Kohno et al, 1995) were suggested as TSGs. Inhibition of caspase 8 in a HNSCC cell line, KB, resulted in the reduction of the apoptotic cell fraction and changes in expression of Fas-related genes after irradiation (Uno et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analyses on Loss of Heterozygosity in Head and Neck Squamous Cell Carcinomas

Beder

Gündüz

Ouchida

et al. 2003

Laboratory Investigation

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SUMMARY:Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor survival rate. Identifying the tumor suppressor gene (TSG) loci by genomic studies is an important step to uncover the molecular mechanisms involved in HNSCC pathogenesis. We therefore performed comprehensive analyses on loss of heterozygosity (LOH) using a genome-wide panel of 191 microsatellite markers in 22 HNSCC samples. We found 53 markers with significantly high LOH (Ͼ30%) on 21 chromosomal arms; the highest values of those were observed on 3p, 9p, 13q, 15q, and 17p, corresponding to D3S2432 (67%), D9S921-D9S925 (67%) and GATA62F03 (86%), D13S1493 (60%), D15S211 (62%), and D17S1353 (88%), respectively. Fifteen hot spots of LOH were defined in 13 chromosomal arms: 2q22-23, 4p15.2, 4q24-25, 5q31, 8p23, 9p23-24, 9q31.3, 9q34.2, 10q21, 11q21-22.3, 14q11-13, 14q22.3, 17p13, 18q11, and 19q12 as loci reported previously in HNSCCs. Furthermore, we identified five novel hot spots of LOH on three chromosomal arms in HNSCC at 2q33 (D2S1384), 2q37 (D2S125), 8q12-13 (D8S1136), 8q24 (D8S1128), and 15q21 (D15S211). In conclusion, our comprehensive allelotype analyses have unveiled and confirmed a total of 20 possible TSG loci that could be involved in the development of HNSCC. These results provide useful clues for identification of putative TSGs involved in HNSCC by fine mapping of the suspected regions and subsequent analysis for functional genes. (Lab Invest 2003, 83:99 -105). Head and neck squamous cell carcinomas (HNSCCs) are a diverse group of cancers and are frequently aggressive in their biologic behavior. They account for 1% to 2% of all cancer deaths in both the United States and Japan. Most patients with this malignancy have advanced disease at presentation, with regional disease in 43% and distant metastases in 10% (Pfister et al, 1997). The overall survival rate for this disease group remains poor, largely because of the high incidence of recurrent disease at the primary site or in the regional lymph nodes. Patients presenting with HNSCC also demonstrate a high incidence of second primary tumors in the upper aerodigestive tract, which may be synchronous or metachronous.In neoplastic progression, most of the sporadic solid tumors result from a multistep process of accumulated genetic and epigenetic alterations (Renan, 1993). Among these changes, inactivation of the tumor suppressor genes (TSGs) is one of the most critical steps. In this process, the deletion of targeted chromosomal regions eliminates the one allele, while inactivating events (mutation, deletion, or promoter hypermethylation) affect the other allele of the concerning TSG (Knudson, 1971). The detection of frequent loss of heterozygosity (LOH) in a chromosomal locus is considered to be critical evidence for the localization of a TSG. Large-scale genomic studies identified the chromosomal locations of several different human TSGs. A substantial number of TSGs involved in the genesis of several cancer types, including HNSCCs, have already been discovered. ...

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“…Thirty-three NSCLC cell lines (A427, A549, Lu65, Lu99, NCI ± H23, NCI ± H157, NCI ± H322, NCI ± H441, NCI ± H520, NCI ± 596, NCI ± H1155, PC3, PC7, PC9, PC10, PC13, Ma1, Ma2, Ma3, Ma10, Ma12, Ma17, Ma24, Ma25, Ma26, Ma29, Ma31, LC1-Sq, RERF ± LCD, RERF ± LCOK, RERF ± LCMS, ABC1 and EBC1) and 19 small cell lung carcinoma cell lines (NCI ± H69, NCI ± H82, NCI ± H209, NCI ± H526, NCI ± H774, NCI ± H841, N230, N231, N417, Lu24, Lu130, Lu134, Lu135, Lu138, Lu139, Lu140, Lu141, SBC-5 and MS18) were used in this study (Kohno et al, 1995). Detailed information on these cell lines can be obtained upon request.…”

Section: Samplesmentioning

confidence: 99%

Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA

Kohno¹,

Shinmura

Tosaka³

et al. 1998

Oncogene

Self Cite

388

309

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The hOGG1 gene encodes a DNA glycosylase that excises 8-hydroxyguanine (oh 8 Gua) from damaged DNA. Structural analyses of the hOGG1 gene and its transcripts were performed in normal and lung cancer cells. Due to a genetic polymorphism at codon 326, hOGG1-Ser 326 and hOGG1-Cys 326 proteins were produced in human cells. Activity in the repair of oh 8 Gua was greater in hOGG1-Ser 326 protein than in hOGG1-Cys 326 protein in the complementation assay of an E. coli mutant defective in the repair of oh 8 Gua. Two isoforms of hOGG1 transcripts produced by alternative splicing encoded distinct hOGG1 proteins: one with and the other without a putative nuclear localization signal. Loss of heterozygosity at the hOGG1 locus was frequently (15/ 23, 62.2%) detected in lung cancer cells, and a cell line NCI-H526 had a mutation leading to the formation of the transcripts encoding a truncated hOGG1 protein. However, the oh 8 Gua levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed. These results suggest that the oh 8 Gua levels are maintained at a steady level, even though multiple hOGG1 proteins are produced due to genetic polymorphisms, mutations and alternative splicing of the hOGG1 gene.

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Identification of a novel phospholipase C family gene at chromosome 2q33 that is homozygously deleted in human small cell lung carcinoma

Cited by 46 publications

References 0 publications

Differential Inactivation of Caspase-8 in Lung Cancers

Differential Inactivation of Caspase-8 in Lung Cancers

Genome-Wide Analyses on Loss of Heterozygosity in Head and Neck Squamous Cell Carcinomas

Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA

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