乳腺癌转移抑制基因1抑制肿瘤转移的机制

乳腺癌转移抑制基因1(BRMS1)具有抑制肿瘤细胞转移的能力,可明显减少转移灶的发生,但不影响肿瘤的生长.其作用机制复杂,与细胞间通讯、磷酸肌醇信号转导以及与转录核因子-KB(NF-KB)的相互作用等有关.故探讨BRMS1抑制肿瘤转移的机制,希望用于肿瘤基因治疗.     

乳腺癌转移抑制基因作用机制

乳腺癌转移抑制基因（BRMS1）在人乳腺癌、黑色素瘤、膀胱癌、卵巢癌、嗜铬细胞瘤中具有抑制肿瘤细胞转移的能力，可明显减少转移灶的发生，作用机制复杂多样而又非典型，成为研究抑制肿瘤转移的新靶点。     

肿瘤转移抑制基因BRMS1的研究进展

肿瘤转移抑制基因是指抑制肿瘤细胞转移而不影响原发肿瘤生长的基因。乳腺癌转移抑制基因1（BRMS1）是在2000年新发现的转移抑制基因,现已发现它能抑制多种肿瘤细胞的转移。本文就BRMS1的基因结构、生物学功能及与多种肿瘤的关系、作用机制及其临床意义作一综述。     

肿瘤浸润,转移与UPA和PAI—1的关系

探索肿瘤转移的分子生物学机制已成为当前人们研究的热点。ＵＰＡ／ＵＰＡＲ系统与纤溶酶原作用，激活局部纤溶机制，导致肿瘤的浸润转移，ＵＰＡ的生理性抑制剂ＰＡＩ－１在其中起到调节作用。ＰＡＩ－１能否作为一种抑制肿瘤转移的作用物，尚待进一步研究。本文就肿瘤浸润转移与ＵＰＡ及ＰＡＩ－１的关系作一综述。     

乳腺癌转移抑制基因作用机制

乳腺癌转移抑制基因(BRMS1)在人乳腺癌、黑色素瘤、膀胱癌、卵巢癌、嗜铬细胞瘤中具有抑制肿瘤细胞转移的能力,可明显减少转移灶的发生,作用机制复杂多样而又非典型,成为研究抑制肿瘤转移的新靶点。     

SIRT1基因在肿瘤中的作用机制

Ⅲ类去乙酰化酶Sirtuin 1(SIRT1)是一种依赖NAD+的组蛋白去乙酰化酶.研究发现SIRT1在肿瘤中的作用具有双面性,它可通过抑制炎症、肿瘤血管形成及与肿瘤相关基因相互作用等机制抑制肿瘤的发生发展;也可通过调控肿瘤相关基因、上皮间质转化、促进肿瘤细胞增殖和肿瘤放化疗耐受以及维持肿瘤干细胞的存活等机制促进肿瘤的增殖、侵袭和转移.     

KiSS-1基因在肿瘤中的研究进展

侵袭和（或）远处转移是影响恶性肿瘤患者预后的关键因素。肿瘤转移涉及肿瘤细胞的侵袭力、黏附力、与间质的相互作用等异常，是多步骤、多因素参与的过程。对肿瘤转移抑制基因的研究已成为肿瘤转移机制研究的热点。Kiss-1是近年克隆的1个新的肿瘤转移抑制基因，研究表明，其表达缺失与人类多种恶性肿瘤转移有关，本文就其在肿瘤中的研究进展作一综述。     

肿瘤相关性中性粒细胞促肿瘤转移机制的研究进展

中性粒细胞是循环中最为丰富的白细胞，在机体的免疫反应中发挥重要作用。中性粒细胞不仅参与免疫反应，也在肿瘤的发生发展，特别是侵袭和转移过程中发挥重要作用。中性粒细胞可分化为N1和N2亚型，在肿瘤的转移中表现出抑制转移（N1）和促进转移（N2）两种截然不同的的作用。但肿瘤相关中性粒细胞（tumor-associated neutrophils，TANs）在肿瘤转移机制中发挥的作用相对比较复杂，尚缺乏系统阐述。本文主要介绍TANs，分析其在肿瘤转移过程中促进肿瘤发生侵袭和转移的机制，对TANs作为抗肿瘤治疗策略的可能性进行综述。      

BRMS1对肿瘤转移抑制机制研究进展

目的:综述乳腺癌转移抑制基因1(BRMS1)在抑制肿瘤转移中的作用机制的研究进展.方法:应用Medline及CNKI期刊全文数据库系统,以“基因、转移抑制和BRMS1”为关键词,检索1996-01-2011-12的相关文献.纳入标准:1) BRMS1的发现及其名称来源;2)BRMS1的结构及其功能;3)BRMS1在肿瘤中的表达;4)BRMS1与肿瘤细胞远处转移关系.根据纳入标准符合分析的文献26篇.结果:BRMS1与其他肿瘤转移抑制基因一样,主要抑制肿瘤的转移,并不影响肿瘤的生长,通过许多复杂的机制,如调节细胞间的缝隙连接信号转导及其他转移抑制基因的表达来抑制转移.结论:对BRMS1基因的深入研究有助于进一步深化对肿瘤转移的认识,为恶性肿瘤的分子诊断和基因治疗提供新的思路.     

肺癌抑制基因1与鼻咽癌

新近发现的肺癌抑制基因1是一种肿瘤抑制基因，位于染色体11q23．2，多项研究表明肺癌肿瘤抑制基因1的低表达与肿瘤侵袭转移及患者预后密切相关。研究表明该基因在鼻咽癌中表达下降或消失，是一种鼻咽癌侯选肿瘤抑制基因。该基因的失活与其启动子区甲基化和杂合子缺失有关，但其在鼻咽癌中发挥抑癌作用的分子机制和细胞内外信号传导通路还有待进一步研究。     

HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression

The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies. Despite the identification of the epigenetical silencing of the NY-ESO1 gene in a large variety of tumors, the molecular mechanism involved in this phenomenon is not fully elucidated. In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes. Thus, our data illustrate the orchestration of a sequential epigenetic mechanism including the histone deacetylation and methylation, and the DNA methylation processes.     

CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility

BACKGROUND: In estrogen biosynthetic pathways, many enzymes are important for metabolism, detoxification, and bioavailability. Polymorphisms in these genes may have an effect on the enzymes' function. For example, higher expression and activation of biosynthetic enzymes and lower expression and activation of conjugation enzymes may lead to high toxicity or carcinogenesis. The authors hypothesized that single nucleotide polymorphisms (single nucleotide polymorphisms) of CYP1A1, CYP1A2, CYP1B1, CYP17, SULT1A1, SULT1E1, and SHBG genes may be risk factors for endometrial cancer. METHODS: DNA samples from 150 cases of endometrial cancer and healthy controls (n = 165) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the genotypic frequency of 13 different polymorphic loci on the CYP1A1 (m1, m2, m3, m4), CYP1A2 1F, CYP1B1 codon432, COMT codon158, CYP17, SULT1A1 (Arg213His, 14A/G, 85C/T in the 3' flanking region), SULT1E1-64G/A promoter region, and SHBG genes. Genotyping was validated by direct DNA sequencing. The authors also investigated the relation between expression of CYP1A1 in endometrial cancer tissues and genotypes of CYP1A1 m1. RESULTS: A decreased frequency of TC + CC genotype of the CYP1A1 m1 (T/C) polymorphism was observed in endometrial cancer patients compared with controls (OR = 0.42; 95% CI, 0.27-0.69). The T-A haplotype of CYP1A1 m1 and m2 was increased in endometrial cancer patients (P = .017). The frequency of CYP1A1 m1 T/C + C/C was higher in a high CYP1A1 expression group (P = .009). The authors also found that individuals carrying the variants of SULT1A1 codon213 and 2 single nucleotide polymorphisms in the 3' flanking region (14A/G and 85C/T) had an increased risk for endometrial cancer. The frequencies of G-A-C and A-G-T haplotypes of these 3 variants were higher in endometrial cancer patients (P < .0001; P = .0002). In addition, the frequency of combined genotypes (SULT1A1 213 GA + AA and CYP1A1 m1 TT) was higher in endometrial cancer patients. (OR, 4.58; 95% CI, 2.35-8.93). CONCLUSIONS: This is the first report on the combined association of CYP1A1 and SULT gene polymorphisms in endometrial cancer that suggests a decreased single nucleotide polymorphism of CYP1A1 and an increased single nucleotide polymorphism for SULT1A1 and SULT1E1 genes may be risk factors for endometrial cancer in Caucasians.     

CYP1A1.

CYP1A1 plays an important role in the metabolism of polycyclic hydrocarbons that occur in the environment and several studies suggest that the genetic polymorphism of the gene may play a role in the predisposition to cancer. In order to evaluate the function of CYP1A1 in vivo as a host factor determinant of environmentally-caused cancers in humans, additional investigations are needed involving not only molecular epidemiological approaches in different ethnic populations but also more direct approaches such as the use of gene-targeted mice as a model system.     

DNA切除修复交叉互补基因1、乳腺癌易感基因、核苷酸还原酶1与非小细胞肺癌

 阐述了近年来非小细胞肺癌（NSCLC）化疗敏感性与DNA 切除修复交叉互补基因1 （ERCC1）、乳腺癌易感基因（BRCA1）、核苷酸还原酶1（RRM1）基因表达关系的研究进展，分析3个基因对NSCLC个体化化疗潜在的指导意义     

Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1

Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) catalyze the oxidative metabolism of 17 beta-estradiol (E2) to catechol estrogens (2-OHE2 and 4-OHE2) and estrogen quinones, which may lead to DNA damage. Catechol-O-methyltransferase catalyzes the methylation of catechol estrogens to methoxyestrogens (2-MeOE2, 2-OH-3-MeOE2, and 4-MeOE2), which simultaneously lowers the potential for DNA damage and increases the concentration of 2-MeOE2, an antiproliferative metabolite. In this study, we showed that CYP1A1 and CYP1B1 recognized as substrates both the parent hormone E2 and the methoxyestrogens. Using purified recombinant enzymes, we demonstrated that CYP1A1 and CYP1B1 O-demethylated the methoxyestrogens to catechol estrogens according to Michaelis-Menten kinetics. Both CYP1A1 and CYP1B1 demethylated 2-MeOE2 and 2-OH-3-MeOE2 to 2-OHE2, whereas CYP1B1 additionally demethylated 4-MeOE2 to 4-OHE2. Because the P450-mediated oxidation of E2 and the O-demethylation of methoxyestrogens both yielded identical catechol estrogens as products, we used deuterated E2 (E2-d4), unlabeled methoxyestrogens, and gas chromatography/mass spectrometry to examine both reactions simultaneously. Kinetic analysis revealed that methoxyestrogens acted as noncompetitive inhibitors of E2 oxidation with K(i) ranging from 27 to 153 micro M. For both enzymes, the order of inhibition by methoxyestrogens was 2-OH-3-MeOE2 > or = 2-MeOE2 > 4-MeOE2. Thus, methoxyestrogens exert feedback inhibition on CYP1A1- and CYP1B1-mediated oxidative estrogen metabolism, thereby reducing the potential for estrogen-induced DNA damage.     

CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure

Certain human biotransformation enzymes have been implicated in the formation and scavenging of the ultimate reactive metabolites, the diolepoxides, from polycyclic aromatic hydrocarbons (PAHs). In the present study, performed on aluminum smelter workers, we have analyzed airborne PAH, the pyrene metabolite 1-hydroxypyrene (1-OHP) in urine, and genotypes for biotransformation enzymes involved in PAH metabolism. The aim was to evaluate the correlation between external exposure and biomarkers of exposure and to investigate to what extent genetic polymorphism in metabolic enzymes can explain interindividual variation in urinary 1-OHP levels. DNA was prepared from blood samples from 98 potroom workers and 55 controls and altogether eight polymorphisms in the CYP1A1, mEH, GSTM1, GSTP1 and GSTT1 genes were analyzed. The 1-OHP excretion was found to correlate significantly (P 100-fold) and univariate and multivariate regression analyses were used to find the variables that could determine differences in excretion. The variation could, to some degree, be explained by differences in exposure to airborne particulate-associated PAHs, the use of personal respiratory protection devices, smoking habits and genetic polymorphisms in the cytochrome P450 1A1, GSTM1 and GSTT1 enzymes. The part of the variance that could be explained by differences in biotransformation genotypes seemed to be of the same order of magnitude as the variance explained by differences in exposure. In the control group as well as in the occupationally exposed group, the highest 1-OHP levels were observed in individuals carrying the CYP1A1 Ile/Val genotype who were also of the GSTM1 null genotype. The results show that urinary 1-OHP is a sensitive indicator of recent human exposure to PAHs and that it may also to some extent reflect the interindividual variation in susceptibility to PAHs.     

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age < or =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.