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1.
Mol Biol (Mosk) ; 43(6): 1088-92, 2009.
Artigo em Russo | MEDLINE | ID: mdl-20088387

RESUMO

Earlier in some small cell lung (SCLC) and non-small cell lung carcinoma (NSCLC) cell lines, methylation of CpG-island was found in the SEMA3B region, which belongs to the first intron according to the NCBI data base (Build 36). The aim of this work was to study methylation of two SEMA3B CpG-islands: promoter and intronic in clear cell renal cell carcinoma (RCC). Using methyl specific PCR and bisulfite sequencing, it was shown for the first time that promoter CpG-island was methylated in RCC with high frequency 56% (34/61), and intronic CpG-island - with somewhat lower frequency 35% (17/48). Significant reverse correlation was estimated between mRNA level decrease and methylation of promoter CpG-island in RCC for the first time (P < or = 0.05 by Fisher's exact test), no correlation was determined for intronic CpG-island. This result suggested that methylation of promoter CpG-island contributed into inactivation of SEMA3B gene-suppressor in RCC.


Assuntos
Carcinoma de Células Renais/metabolismo , Ilhas de CpG , Metilação de DNA , Neoplasias Renais/metabolismo , Glicoproteínas de Membrana/biossíntese , Regiões Promotoras Genéticas , Semaforinas/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Íntrons/genética , Neoplasias Renais/genética , Glicoproteínas de Membrana/genética , Semaforinas/genética , Proteínas Supressoras de Tumor/genética
2.
Mol Biol (Mosk) ; 38(6): 1005-13, 2004.
Artigo em Russo | MEDLINE | ID: mdl-15612586

RESUMO

The methylation level of 13 CpG-dinucleotides in the promoter region of the putative tumor suppressor gene RASSF1A (3p21.31) was analyzed in HPV-positive squamous cell carcinomas of cervix using methyl-sensitive restriction endonuclease analysis followed by PCR. The methylation from 3 to 13 CpG-dinucleotides was observed in 64% (25/39) tumors, 22% (2/9) morphologically normal tissues adjacent to tumors (P = 0.0306) and in 2 from 3 leucocytes of peripheral blood of patients. The methylation of these CpG-dinucleotides was absent in DNA of healthy donor leucocytes (0/10). Methylation level of the examined fragment of the RASSF1A promoter region was significantly higher in tumors of patients with lymph node metastases in comparison to tumors of patients without metastases (P = 8.5 x 10(-12)). The methylation frequency of RASSF1A gene was in two times higher than hemi- and homozygous deletion frequency at the region of location of this gene (chromosome 3p21.31), determined earlier. These data suggest that methylation of the RASSF1A gene is one of the main ways of this gene inactivation in HPV-positive cervical squamous cell carcinomas. The methylation of the RASSF1A gene is an early event in genesis of tumor and the level of methylation increased with tumor progression.


Assuntos
Carcinoma de Células Escamosas/genética , Metilação de DNA , Genes Supressores de Tumor , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Sequência de Bases , Carcinoma de Células Escamosas/patologia , Cromossomos Humanos Par 3 , Primers do DNA , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase , Neoplasias do Colo do Útero/patologia
3.
Mol Biol (Mosk) ; 38(4): 654-67, 2004.
Artigo em Russo | MEDLINE | ID: mdl-15456137

RESUMO

Methylation of the promoter CpG-islands of the candidate tumor suppressor gene RASSF1A (3p21.31) was studied in primary tumors of kidney, breast and ovary (172 cases). Methylation-specific PCR (MSP) and methyl-sensitive restriction endonuclease digestion followed by PCR (MSRA) were applied. Statistically significant correlation (P << 10(-6)) was shown for the results of the MSP and MSRA, and the data of bisulfite sequencing reported earlier. The frequency of RASSF1A methylation according to MSP and MSRA was 86% (25/29) and 94% (50/53) in renal cell carcinoma (RCC) and 64% (18/28) and 78% (32/41)--in breast carcinoma (BC) samples, and 59% (17/29) and 73% (33/45) in ovarian epithelial tumors (OET), respectively. The use of several methyl-sensitive restriction enzymes (HpaII, HhaI, Bsh12361, AciI) enhanced the sensitivity of MSRA and allowed to analyze methylation status of 18 CpG-pairs in the RASSF1A CpG-island. Density of methylation of the RASSF1A CpG-island was 72% (644/900) in RCC, 63% (361/576) in BC, and 58% (346/594) in OET samples (18 CpG-pairs multiplied to the number of samples shown methylation were assumed as 100%). The RASSF1A gene methylation was also observed in samples of morphologically normal tissues adjacent to corresponding tumors (11-35%), but it was not detected in blood DNAs of healthy donors (0/15). The RASSF1A methylation frequency did not show significant correlation to tumor stage, grade and metastases (P = 0.3-1.0). The RASSF1A gene methylation was observed more frequently than other investigated aberrations--hemi- and homozygous deletions inside or around this gene. These observations are consistent with the hypothesis that the RASSF1A gene methylation is an early event in the carcinogenesis and one of the dominant ways of its inactivation.


Assuntos
Metilação de DNA , Neoplasias/genética , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Alelos , Sequência de Bases , Ilhas de CpG , DNA/química , DNA/metabolismo , Humanos , Hidrólise , Dados de Sequência Molecular , Peso Molecular
4.
Mol Biol (Mosk) ; 37(2): 194-211, 2003.
Artigo em Russo | MEDLINE | ID: mdl-12723467

RESUMO

Studies of the recent decade, including sequencing of numerous human genome regions, allowed a great progress in detection of new tumor suppressor genes (TSG) and development of new means of their identification and analysis. Effective methods of genome scanning and TSG identification combine DNA array techniques and subtraction hybridization. Alternative ways take advantage of new extrachromosomal vector systems (pETE, pETR) and the functional gene inactivation test. A breakthrough was made in localizing new TSG on the human chromosome 3 short arm, which harbors tumor-suppressing regions and is often rearranged in various tumors and in early carcinogenesis. On 3p, only three putative TSG were known five years ago, and at least ten were identified by the end of 2002. The role of new TSG in carcinogenesis is commonly inferred from a decrease in their transcription in tumor cell lines or primary tumors and from their ability to suppress the growth of these. Protein products of 3p TGS play an important part, constraining cell malignization. Some are directly involved in regulating the cell cycle and inducing apoptosis (RASSFIA), others suppress angiogenesis (Sema3B) or metastasis (Hyal-1). Numerous attempts to find mutations in exons of silent genes failed, and at least half of the new candidate genes (RASSFIA, CACNA2D2, BLU, HYAL1, SEMA3B, RAR-beta) proved to be inactivated by promoter methylation.


Assuntos
Cromossomos Humanos Par 3 , Genes Supressores de Tumor , Técnicas Genéticas , Proteínas Supressoras de Tumor , Adenoviridae/genética , Apoptose/genética , Metilação de DNA , Desoxirribonucleases de Sítio Específico do Tipo II/genética , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Terapia Genética/métodos , Vetores Genéticos , Humanos , Hibridização In Situ/métodos , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neovascularização Patológica/genética , Precursores de Proteínas/genética , Semaforinas , Deleção de Sequência , Transdução Genética , Ubiquitinas/genética
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