SULT1A1 蛋白表达和性激素含量与子宫肌瘤发病相关性的研究

目的：检测子宫肌瘤SULT1A1蛋白表达和性激素含量,分析其在子宫肌瘤发生、发展中的作用.方法：化学发光分析法测定30例子宫肌瘤患者、30例同年龄段健康女性以及10例因CINⅢ行全子宫切除术患者血清及组织匀浆中E2、P、T含量.Western Blot方法检测 SULT1A1蛋白的表达,并采用Spearman进行等级相关分析.结果：肌瘤组血清E2含量明显低于健康女性组（P＜0.05）,其T含量则明显高于健康女性组（P＜0.01）,P含量各组无显著差异.肌瘤组织E2含量显著高于肌瘤包膜外子宫肌层组织及CINⅢ患者子宫肌层组织（P＜0.001）、前二者P、T含量组间无显著差异.肌瘤组织中SULT1A1蛋白表达与肌瘤包膜外子宫肌层组织比较差异显著（P＆lt;0.05）.肌瘤组织,肌瘤包膜外子宫肌层组织和CINⅢ患者子宫肌层组织中SULT1A1蛋白相对含量与相应组织匀浆E2含量均为负相关,与相应血清E2含量无明显相关性.结论：子宫肌瘤的发生、发展与子宫肌瘤组织局部SULT1A1蛋白活性降低有关.     

SULTIE1蛋白表达和性激素含量与子宫肌瘤发病的相关性研究

目的：探讨性激素及人雌激素硫酸基转移酶在子宫肌瘤发生、发展中的作用。方法：化学发光分析法测定30例子宫肌瘤患者和30例同年龄段健康女性血清及组织匀浆中E2、P、T含量。免疫组化染色法检测SULTIE1蛋白的表达。结果：肌瘤组血清E2含量明显低于健康女性组（P〈0．05）,其T含量则明显高于健康女性组（P〈0．05）,P含量各组无显著差异;肌瘤组织匀浆中E2含量显著高于肌瘤包膜外肌层组织（P〈0．01）,其P、T含量两组间无显著差异;肌瘤组织中SULTIE1蛋白表达与肌瘤包膜外肌层组织比较差异显著（P〈0．05）,肌瘤组织与肌瘤包膜外肌层组织中SULTIE1蛋白定量表达与相应组织匀浆中E2含量分别呈负相关（r=-0．533,r=-0．498,P〈0．01）。结论：子宫肌瘤的发生、发展与子宫肌瘤组织局部SULTIE1酶活性降低有关。     

SULT1E1、ERβ在子宫内膜腺癌组织中的表达及其相关性

目的:探讨SULT1E1及ERβ蛋白与子宫内膜腺癌的发生、发展之间的关系。方法:采用Western blot方法检测正常增生期子宫内膜组织、不典型增生子宫内膜组织及子宫内膜腺癌组织中SULT1E1和ERβ蛋白的表达含量。结果:SULT1E1和ERβ蛋白在正常增生期子宫内膜组织、不典型增生子宫内膜组织及子宫内膜腺癌组织中的表达含量逐渐降低,三者比较差异有统计学意义(P<0.05)。不典型增生子宫内膜组织及子宫内膜腺癌组织与正常增生期子宫内膜组织比较差异均有统计学意义(P<0.05)。SULT1E1和ERβ蛋白与子宫内膜腺癌组织学分级、肌层浸润深度、手术病理分期及淋巴结转移等无关(P>0.05)。在子宫内膜腺癌组织中,SULT1E1蛋白与ERβ蛋白表达呈明显正相关(r=0.66,P<0.01)。在正常增生期和不典型增生子宫内膜组织中,SULT1E1蛋白与ERβ蛋白表达无明显相关性(r=0.035,P>0.05;r=0.466,P>0.05)。结论:在子宫内膜腺癌的渐近演变过程中,SULT1E1、ERβ表达降低或缺失可能与子宫内膜癌的早期形成有一定的关系,ERβ蛋白含量越多,SULT1E1蛋白对雌激素的调节作用越强,但不能作为子宫内膜腺癌病情严重程度和预后进行评价的指标。     

SULT1A1基因Arg213His位点多态性与子宫肌瘤发生的关联性

目的：探讨硫酸氨基转移酶 （Sulfotransferase, SULT） 1A1基因Arg213His位点多态性与鲁北地区汉族女性子宫肌瘤的关系。方法： 以病例-对照的研究方法, 采用聚合酶链式反应-限制性片段长度多态性 （PCR-RFLP） 方法检测了123例子宫肌瘤患者和123例匹配对照者的SULT1A1基因Arg213His位点的基因型, 应用条件Logistic回归等方法分析基因多态性与子宫肌瘤的关系。结果： 1） SULT1A1基因Arg/Arg、 Arg/His、 His/His 3种基因型在子宫肌瘤与对照组中的分布存在显著性差异 （P=0.011）; 2） 与Arg/Arg基因型相比, Arg/His、 His/His危险度均增加, 分别为2.321倍和1.985倍 （P=0.003和P=0.468）; 3） His等位基因可显著增加患子宫肌瘤的危险性 （P=0.003, OR调整=2.296, 95%CI为1.325～3.978）。结论： SULT1A1基因Arg213His位点基因多态性与鲁北地区汉族女性子宫肌瘤的发生有关, 增加了子宫肌瘤的患病风险。     

乳腺癌组织SULT1E1蛋白表达与临床病理学特征及预后相关性的研究

目的:探讨乳腺癌组织SULT1E1的表达,并分析其与临床病理学特征及预后因素的相关性.方法:采用免疫组织化学二步法检测129例乳腺癌组织和癌旁正常组织SULT1E1的表达情况,应用Kaplan-Meier法行单因素生存分析SULT1E1的表达与临床病理学特征及预后的关系.结果:乳腺癌组织中SULT1E1的阳性表达率(25.6％)明显低于癌旁组织(45.0％),差异有统计学意义,P＜0.05;SULT1E1的表达与乳腺癌患者年龄、肿瘤大小、淋巴结转移和病理类型以及是否有远处转移等无明显相关性,P＞0.05.Kaplan-Meier生存分析曲线显示,SULT1E1阳性表达患者的术后无复发生存率较阴性表达患者明显增高,x2=4.943,P＜0.05.结论:乳腺癌组织SULT1E1低表达者提示预后不佳,SULT1E1检测有可能成为判断乳腺癌分期和预后的重要分子标志,并成为重要的预后因素.     

性激素在子宫内膜间质细胞的作用—子宫肌瘤发生机理的初探

目的：探讨性激素对子宫肌瘤的发生和生长的调节作用。方法：采用体外子宫内膜间质细胞培养，加以雌二醇（E2）、孕酮（P）、睾酮（T）刺激后，进行流式细胞学测定其细胞周期和凋亡的动力学变化。结果：T单独作用对其促进DNA合成及有丝分裂效果最明显，但与E2或P合用时其作用大大削弱；而E2 P对细胞DNA合成及有丝分裂的促进作用比单用E2强，两者的这种协同作用在有T存在的情况下也被减弱。P对细胞的G2 M期作用最强。T对细胞凋亡具有促进作用，T和P之间存在拮抗作用，P能够抑制细胞凋亡。结论：雌孕激素与雄激素之间的代谢平衡对于维持细胞的正常功能至关重要，若局部组织细胞增生与凋亡失衡则会导致肿瘤的发生。     

血清性激素水平和体重指数与绝经后女性乳腺癌发病的相关性研究

目的 探讨绝经后女性乳腺癌的发病与血清性激素水平和体重指数的关系。方法 选择2013年3月—12月在哈尔滨医科大学附属肿瘤医院乳腺外科接受手术治疗的初诊绝经后乳腺癌118例作为病例组以及60例绝经后乳腺良性病变者作为对照组,并收集所有受试对象的身高、体重等基本资料。应用酶联免疫吸附实验(ELISA)方法检测受试对象的血清雌二醇(Estradiol,E2)、雌酮(Estrone,E1)、睾酮(Testesterone,TSTO)以及雄烯二酮(Androstenedione,AED)水平,并对结果进行分析。结果 病例组血清E2、E1、AED水平显著高于对照组(P＜0.05),病例组的血清TSTO平均水平稍高于对照组,但差异无统计学意义(P＞0.05);病例组体重指数(BMI)与对照组无明显差异(P＞0.05);病例组血清E1以及总研究对象的血清E1、TSTO、AED在超重组内的水平明显高于非超重组(P＜0.05),未发现其余各组的激素水平与BMI指数具有相关性(P＞0.05)。结论 绝经后女性乳腺癌患者的血清性激素水平升高,血清E2、E1、AED水平升高可能是与绝经后女性乳腺癌的发病相关,BMI高的绝经后女性的血清性激素水平较高。     

子宫肌瘤患者血清性激素水平的Meta分析

目的:系统评价子宫肌瘤患者与非子宫肌瘤患者血清雌激素、孕激素、卵泡刺激素（FSH）、黄体生成素（LH）水平的差异,为子宫肌瘤的发病风险评估及临床诊治提供依据。方法:计算机检索1995年至今在Pubmed、CNKI、万方、维普等数据库公开发表的相关文献,根据Newcastle-Ottawa Scale（NOS）量表对入选文献进行质量评价,采用 Revman 5.3软件绘制森林图,Stata12.0软件进行敏感性分析和发表偏倚评估。结果:共纳入17篇研究,累计子宫肌瘤患者1549例,对照组863例,计算合并SMD及其95% CI,Meta分析结果显示,子宫肌瘤患者卵泡期血清FSH（SMD= 0.34,95%CI: 0.10～0.59,P= 0.006）、LH（SMD= 0.40,95%CI: 0.24～0.55,P< 0.00001）水平高于对照组,而卵泡期血清雌激素、孕激素及黄体期血清雌激素、孕激素、FSH、LH水平与对照组相比无明显统计学差异。结论：卵泡期血清FSH、LH水平较高的女性有更高的子宫肌瘤发病风险,卵泡期血清雌激素、孕激素和黄体期血清雌激素、孕激素、FSH、LH水平与子宫肌瘤的发生无显著联系。     

一氧化氮合成酶在子宫肌瘤的表达及与性激素的关系

[目的]探讨一氧化氮(NO)与子宫肌瘤生长及其与雌激素(E)、孕激素(P)的关系。[方法]36例手术治疗的子宫肌瘤,术后测定肌瘤组织一氧化氮合成酶(NOS)的活性、雌激素受体(ER)、孕激素受体(PR)水平及血管管径大小,自身子宫肌层组织作为对照组。[结果]子宫肌瘤组织中的NOS活性及ER、PR含量均明显高于子宫肌层组织(P<0.05);而且NOS的活性与ER呈正相关(r="0.43,"P<0.05),与PR无相关(r="0.24,"0.05);肌瘤组织中的NOS活性与肌瘤内血管管径的大小呈正相关(r=0.33,P<0.05)。[结论]NOS与子宫肌瘤的生长有关,可能通过E增加NOS活性,使肌瘤局部血管舒张,增加血流量,增加肌瘤细胞的代谢和营养,促使肌瘤生长。     

SULT1A1基因多态性与女性乳腺癌易感性及他莫昔芬治疗预后相关性研究

目的探讨SULT1A1基因多态性与女性乳腺癌易感性及他莫昔芬治疗预后相关性。方法选择女性乳腺癌患者86例作为研究组,选择同期健康女性80例作为对照组,通过电子病历调查收集其一般资料。采用限制性片段长度多态性聚合酶链反应法检测两组患者外周血SULT1A1基因rs9282861位点多态性,对携带不同基因型患者预后进行比较。结果研究组rs9282861位点GA、AA基因型、A等位基因频率高于对照组(P<0.05),GG基因型、G等位基因频率低于对照组(P<0.05);Logistic回归分析结果显示,与携带GG基因型患者相比,携带GA、AA、GA+AA患者发生乳腺癌风险分别为3.125、3.938、3.450倍,与携带G等位基因患者相比,携带A等位基因患者发生乳腺癌风险为3.008倍,均具有统计学意义(P<0.05);所有患者中位生存期为26个月,rs9282861位点GG、GA、AA基因型中位生存时间分别为30个月、24个月、20个月,差异具有统计学意义(P<0.05)。结论SULT1A1基因rs9282861位点与本地区女性乳腺癌易感性及他莫昔芬治疗预后存在关联,参与了乳腺癌的发生、发展过程。     

Estrogen sulfotransferase (SULT1E1) expression in benign and malignant human bone tumors

BACKGROUND AND OBJECTIVES: 17beta-estradiol regulates growth and differentiation in normal and malignant bone. E2 is inactivated to 17beta-estradiol-sulfate through estrogen sulfotransferase (SULT1E1). RESULTS: In an explorative study, SULT1E1 mRNA expression was assessed in a broad range of samples from benign, primary and secondary malignant bone tumors. We detected SULT1E1 mRNA in 31/50 tumor samples (10/19 malignant, 6/13 benign tumors; 15/18 metastases). Significantly more SULT1E1-positive samples were found in metastases than in primary bone tumors (P = 0.019). Yet, there was no difference between malignant and benign primary tumors (P = 0.718). SULT1E1 mRNA levels were not related to patients' age, gender, tumor location, stage, grading, and chemotherapy pretreatment. Relative SULT1E1 mRNA levels did not correlate with that of estrogen-receptor alpha (ERalpha) as assessed by quantitative TaqMan PCR (10 malignant, 8 benign tissue samples). In the latter, ERalpha mRNA, but not SULT1E1 mRNA levels were significantly lower than in the malignant samples (P = 0.006 and P = 0.71, respectively). Also, pronounced expression of SULT1E1 mRNA but not of ERalpha mRNA was observed in osteosarcoma (MG-63, HOS) and Ewing's sarcoma (TC-71) cells, while human osteoblasts and BMSC contained ERalpha but not SULT1E1 mRNA. CONCLUSION: Frequent expression of SULT1E1 mRNA in various human bone tumors suggests that sulfonation might be important to control E2 levels and activity.     

SULT1A1 polymorphism and esophageal cancer in males

Sulfotransferase (SULT) 1A1 detoxifies and bioactivates a broad spectrum of substrates including xenobiotics. It has been suggested that the SULT1A1 his (histidine) allele, which is caused by a his for arg (arginine) substitution due to a G-->A transition at codon 213, carries a significantly higher risk for women to develop breast cancer. We investigated the association between the SULT1A1 arg/his genotype and esophageal cancer in men, 187 cases of esophageal squamous cell carcinoma and 308 controls from 3 medical centers in Taiwan. Cigarette smoking, areca chewing and alcohol consumption were the major risks for developing esophageal cancer. The frequencies of arg/his in cases and controls were 27.8% (52/187) and 11.0% (34/308), respectively (p < 0.0001). No subjects carried his/his. After adjusting for substance use and other covariates, individuals with arg/his had a 3.53-fold higher risk (95% CI = 2.12-5.87) of developing esophageal cancer than those with arg/arg. Unexpectedly, this positive association was found to be even stronger (adjusted OR = 4.04-4.80) among non-smokers, non-drinkers or non-chewers. Our findings suggest that the SULT1A1 his(213) allele is important in the development of esophageal cancer in men.     

SULT1A1 genotype and susceptibility to colorectal cancer

Several procarcinogens that are present in cooked red meat and tobacco smoke are substrates for sulfotransferase 1A1 (SULT1A1). The association between environmental exposures and colorectal cancer risk may be modified by individual differences in the metabolism. Thus, we investigated the effect of a common polymorphism in the SULT1A1 gene associated with decreased enzyme activity on the susceptibility to colorectal cancer in a population-based case-control study. Patients (505) and 604 age- and sex-matched controls provided detailed risk factor information and were genotyped for SULT1A1 G638A using a fluorescence-based melting curve analysis method. Multivariate logistic regression analysis was used to estimate colorectal cancer risk associated with environmental exposures by SULT1A1 genotype. SULT1A1 genotype was not an independent risk factor for colorectal cancer. Risk of colorectal cancer associated with frequent consumption of red meat was significantly elevated among carriers of the SULT1A1*2 allele but not increased among subjects with the SULT1A1*1/*1 genotype (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-4.1 and OR 1.0, 95% CI 0.5-2.1, respectively). Colorectal cancer risk associated with 30+ pack-years of active smoking was higher among carriers of the SULT1A1*2 allele (OR 1.7, 95% CI 1.0-3.2) than among individuals with the SULT1A1*1/*1 genotype (OR 1.1, 95% CI 0.6-2.1). Our results do not support a main effect of SULT1A1 genotype with regard to colorectal cancer but suggest that individuals with the low activity SULT1A1*2 allele may be at higher risk following carcinogen exposure than those with the SULT1A1*1/*1 genotype.     

Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism.

BACKGROUND: Tamoxifen is hydroxylated by cytochrome P450 (CYP) 2D6 to the potent metabolites 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam), which are both conjugated by sulphotransferase (SULT)1A1. Clinical studies indicate that CYP2D6 and SULT1A1 genotypes are predictors for treatment response to tamoxifen. Therefore, we examined the relationship between CYP2D6 genotype, SULT1A1 genotype, SULT1A1 copy number and the pharmacokinetics of tamoxifen. PATIENTS AND METHODS: The serum levels of tamoxifen and metabolites of 151 breast cancer patients were measured by high-pressure liquid chromatography-tandem mass spectrometry. The CYP2D6 and SULT1A1 polymorphisms and SULT1A1 copy number were determined by long PCR, PCR-based restriction fragment length polymorphism, DNA sequencing and fluorescence-based PCR. RESULTS: The levels of 4OHtam, 4OHNDtam and N-demethyltamoxifen were associated with CYP2D6 predicted enzymatic activity (P < 0.05). The SULT1A1 genotype or copy number did not influence the levels of tamoxifen and its metabolites. However, the ratios of N-demethyltamoxifen/tamoxifen and N-dedimethyltamoxifen/N-demethyltamoxifen were related to SULT1A1 genotype. CONCLUSION: CYP2D6 and SULT1A1 genotypes may partly explain the wide inter-individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.     

SULT1A1 Arg213His polymorphism and lung cancer risk: a meta-analysis

Background: The SULT1A1 Arg213His polymorphism is reported to be associated with lung cancer risk. However, this relationship remains controversial. For better understanding a meta-analysis was therefore performed. Methods: An extensive search was performed to identify all case-control studies investigating association between SULT1A1 Arg213His polymorphism and lung cancer risk. The strength was assessed by odds ratio (OR) with the corresponding 95% confidence interval (95%CI). Results: A total of five publications covering 1,669 cases and 1,890 controls were included in this meta-analysis. No significant association between SULT1A1 Arg213His polymorphism and lung cancer risk was observed in overall comparisons in all genetic models (dominant model: OR=1.33, 95%CI=1.00-1.76, P=0.05; additive model: OR=1.30, 95%CI=0.93-1.81, P=0.12; recessive model: OR=1.21, 95%CI=0.89-1.66, P=0.23). However, on subgroup analysis, an elevated risk in mixed populations with variant His allele was revealed in the dominant model (OR=1.66, 95% CI=1.06-2.62, P=0.03). Furthermore, the SULT1A1 Arg213His polymorphism was associated with an increased risk of lung cancer in both females and males in the dominant model (females: OR=1.72, 95%CI=1.29-2.27, P=0.00; males: OR=1.46, 95%CI=1.19-1.78, P=0.00). No significant association between this polymorphism and different smoking status (smokers and non-smokers) and the other ethnicities (Asians and Caucasians) was shown. Conclusions: The results of this meta-analysis indicate that the SULT1A1 Arg213His polymorphism is not associated with lung cancer risk in Asians and Caucasians, but possible elevation for genotype (GA/AA) in mixed populations and males and females needs further investigation.     

SULT1E1 and ID2 genes as candidates for inherited predisposition to breast and ovarian cancer in Jewish women

Mutations in currently known genes account for only a subset of breast/ovarian cancer risk families. Three loci (2p, 4q, 22q) seemingly harbor breast cancer susceptibility genes. To explore their putative role in Jewish women, 46 affected women representing 22 high risk families were genotyped with D2S2211, D4S392, D22S278 and D22S283 and two flanking markers for each locus, and mutational analysis of ID2 (Chromosome 2) and SULT1E1 (Chromosome 4) genes was carried out in seemingly linked families. No ID2 gene mutations were detected in 8 women from the 4 families seemingly linked to D2S2211, whereas a missense mutation (His224Gln) in one affected woman from a single family was detected among 9 women from the 4 families linked to D4S392. This mutation was not found among 153 high risk, 98 sporadic breast/ovarian cancer patients, or 97 healthy controls. The SULT1E1 gene may need to be further explored as candidate breast cancer gene.