性激素依赖性肺癌女性患者的筛选及其临床意义
发布时间：2018-07-16 11:24
【摘要】：非小细胞肺癌无论在男女肿瘤中都具有较高的发病率和极高死亡率。近些年来,男性肺癌患者的发病达到平台期,女性肺癌发病率却逐年上升。2014年全国肿瘤登记中心发布的数据显示:我国2010年女性新增肺癌发病病例为18.96万,居女性第2位恶性肿瘤,占女性新发恶性肿瘤的14.75%。女性肺癌出现年轻化、发病率高的不同特点。这类女性肺癌大多无抽烟史,而且腺癌更多。虽然女性肺癌患者的发病增多,部分研究归因于女性抽烟人群的增多、女性烹调油烟或被动抽烟、女性对烟雾的易感性、人乳头瘤病毒(HPV)感染或现代社会女性生活压力增大造成的影响。但部分文献研究却得不到此种结论。不容忽视的是烟雾对肺癌影响是以鳞癌发病为主要表现的。以腺癌为主的女性肺癌增多和年轻化是很难解释的。男女之间性别差异影响着非小细胞肺癌发生、疾病进展和分子生物学不同特性,并决定治疗效果和预后。男女之间最大区别为性激素不同。性激素中最主要激素是雌激素。雌激素(Estrogen)是一种甾体类固醇性激素,人体中的雌激素有三种:雌二醇、雌三醇和雌酮。其中雌二醇活性最强。女性雌激素主要由卵巢的卵泡分泌,少量由女性怀孕后的胎盘产生,和雌激素受体具有高度的亲和力。在绝经后女性中,卵巢不再产生雌激素素,血清雌二醇水平显著下降。研究表明雌激素在体内或体外试验中都可诱导肿瘤细胞的增殖,抗雌激素药物可以阻断这种作用。其次是孕激素,孕激素也是女性甾体激素,由卵巢黄体产生的孕激素是孕酮。促黄体生成素(LH)是垂体前叶嗜碱性细胞分泌的一种糖蛋白激素,主要是促进卵巢排卵,在FSH的协同作用下,形成黄体并分泌孕激素。促卵泡生成激素(FSH)是垂体前叶嗜碱性细胞分泌的一种糖蛋白激素,其主要功能是促进卵巢的卵泡发育和成熟。由卵巢的黄体分泌,主要功能是促使子宫内膜从增殖期转变为分泌期。雌激素受体(ER)和孕激素受体(PR)与乳腺癌和子宫内膜癌相关,在乳腺癌组织中雌、孕激素受体状况是判断乳腺癌和子宫内膜癌预后及给予激素治疗的重要依据。雌、孕激素受体的检测用于指导乳腺癌的内分泌治疗,已在临床上广泛采用并取得了显著的疗效,改善了乳腺癌和子宫内膜癌患者的预后。因此把乳腺癌等依赖性激素靶器官肿瘤称为性激素依赖性肿瘤。不仅如此,在非性激素靶器官的肿瘤组织中存在性激素受体,以往研究表明正常人及肺癌患者的肺组织中均存在性激素受体,肺癌组织中的性激素受体水平明显高于正常人,提出肺癌也是性激素依赖性肿瘤。雌激素受体存在两个亚型,为雌激素受体α(ERα)和雌激素受体β(ERβ)。在以往研究中ERα在肺癌中表达还存在争议,但大部分认为ERα在肺癌中表达不明显,肺癌肿瘤中主要表达为ERβ。ERβ在肺癌的发生发展中具有重要作用,特别在以性别作为影响因素性激素依赖性肿瘤中具有重要影响。雌激素及其受体在肿瘤中作用机制可能为:雌激素进入肿瘤细胞质以后和特异性受体结合,形成激素受体复合物。激素受体复合物可以穿过核膜,进入细胞核,和核内受体结合并单体二聚化。从而影响细胞核中脱氧核糖核酸(DNA)的转录,合成了新的蛋白质,形成了新的肿瘤。虽然抗雌激素治疗在体外实验或动物实验中取得良好效果。但是,大部分女性肺癌患者给予抗性激素治疗后,并没有得到较好的疗效和取得更长的生存时间,这成为靶向抗雌激素治疗不足。可能为性激素依赖型肺癌患者的判断和筛选条件影响了此类患者的治疗。这样,对性激素依赖型肺癌判断和筛选条件成为首要研究方向。通过研究我们发现ERβ可能是性激素依赖性女性肺癌的一个重要因素。同时绝经前雌激素升高和绝经后孕激素的降低也可能是性激素依赖性肺癌的一个重要因素。通过合成针对ERβ的si RNA并构建与之相应的载体,对生长期培养的ERβ高表达的的细胞株LTEP-a2进行转染,对比阴性对照组和空白对照组;RT-PCR检测转染细胞ERβm RNA的表达,Western blot法检测ERβ蛋白的表达。噻唑蓝比色法(MTT法)检测雌激素培养的转染的细胞生长,流式细胞仪检测培养的转染的肺癌细胞的凋亡情况。在体外试验中佐证了ERβ可能是性激素依赖性肺癌的一个重要因素。通过抗性激素治疗效果作为判断女性性激素依赖性肺癌的依据,探讨其与一般情况及病理学因素之间的相互关系,筛选女性非小细胞肺癌性激素依赖性患者的影响因素。单因素分析筛选出与女性性激素依赖性肺癌相关因素,Logistic回归分析进一步筛选判断。肺癌发生发展是一个复杂的过程,性激素依赖性女性肺癌提出也是一个新的课题。针对性激素和相关受体及其相关机制的研究,有助于实现肺癌个性化诊断和治疗。本研究尝试从不同方面寻找此类患者的筛选条件,为女性非小细胞肺癌提供一种新的治疗方法。本研究包括以下四个部分章节第一部分:女性非小细胞肺癌患者雌激素受体的表达及其临床意义目的:检测女性非小细胞肺癌患者雌激素受体表达,研究其与病理学因素及术后生存率的关系,探讨女性非小细胞肺癌患者雌激素受体表达的临床检测价值。方法:应用免疫组化法检测2007年3月至2012年05月江门市中心医院手术的125例女性非小细胞肺癌患者肿瘤标本中雌激素受体ERα和ERβ,孕激素受体A(PRA)和孕激素受体(PRB)表达,分析其影响因素。Kaplan-Meier生存曲线比较生存率。结果:1.125例非小胞肺癌患者ERα阳性0例,所有肺癌肿瘤细胞未发现ERα阳性。125例非小胞肺癌患者ERβ阳性58例,阳性率为46.4%。2.125例非小胞肺癌患者PRA阳性0例,PRB阳性0例,所有肺癌肿瘤细胞未发现PRA阳性和PRB阳性。3.ERβ阳性表达与年龄大小、绝经前后状态、肺癌的病理类型、分期有关,其中腺癌的阳性率最高,鳞癌的阳性率最低。随着分期增高,ERβ阳性表达也越高(P0.05)。ERβ阳性表达与肿瘤大小、分化程度、有无吸烟史无显著差异(P0.05)。4.绝经前ERβ阴性患者生存率明显高于绝经前ERβ阳性女性非小细胞癌(P0.05);绝经后ER?阳性生存率明显高于绝经后女性非小细胞肺癌(P0.05)。结论:1.检测女性非小细胞肺癌患者雌激素受体表达具有重要意义,可以有助于了解女性患者的术后生存情况,给此类患者术后综合治疗提供综合判断。2.肿瘤组织雌激素受体ERβ水平可以影响女性非小细胞肺癌生长和术后生存,可能是女性性激素依赖性非小细胞肺癌筛选的一个重要因素。第二部分:女性非小细胞肺癌患者外周血性激素水平与癌组织雌激素受体表达的关系目的:女性非小细胞肺癌患者呈现增多和年轻化的趋势,研究表明肺癌也为性激素依赖性肿瘤,性激素在女性非小细胞肺癌发生发展中具有重要影响。研究女性非小细胞肺癌患者癌组织中雌激素受体β表达与外周血性激素水平,探讨其相关性及其临床意义。方法:应用磁性微粒分离的免疫酶联分析检测2006年3月至2012年05月中山大学附属江门医院手术的94例绝经前和128例绝经后女性非小细胞肺癌患者外周血性激素雌二醇(E2),卵泡生成激素(FSH),黄体生成激素(LH),孕酮(P)水平,术后免疫组化法检测肿瘤标本中雌激素受体ERβ表达,分析其相互关系。结果:1.绝经前94例女性非小细胞肺癌患者ERβ表达阳性为36例,阳性率为38.29%;绝经后128例女性非小细胞肺癌患者ERβ表达阳性为47例,阳性率为36.72%。2所有女性患者孕激素受体PRA和PRB均为阴性,阳性率为0。3.绝经前女性非小细胞肺癌患者血清E2正常组中79例患者54例ERβ无明显表达,25例等级表达;升高组中15例患者4例ERβ无明显表达,11例等级表达。绝经前女性非小细胞肺癌患者血清E2正常组和升高组之间雌激素受体β表达有统计学意义(p0.05)。4.绝经前女性非小细胞肺癌患者血清FSH、LH正常组和升高组雌激素受体表达无差异。血清P正常组和降低组雌激素受体表达无差异(p0.05)。5.绝经后女性非小细胞肺癌患者血清P正常组中107例患者75例ERβ无明显表达,32例等级表达;降低组中21例患者6例ERβ无明显表达,15例等级表达。绝经后女性非小细胞肺癌患者血清P正常组和降低组雌激素受体表达有统计学意义(p0.05)。6绝经后女性非小细胞肺癌患者血清E2、FSH、LH正常组和升高组雌激素受体表达无差异。(p0.05)。结论:1.女性非小细胞肺癌患者外周血存在性激素代谢的紊乱和失衡。2.绝经前雌激素异常可能影响雌激素受体表达,绝经后孕激素异常可能影响雌激素受体表达。3.无论绝经前期还是后期,LH和FSH激素的变化和肿瘤内雌激素受体表达无差异。4.绝经前血清中雌激素升高影响和绝经后孕激素降低都可以影响雌激素受体表达,可能为性激素依赖性肺癌的一个影响因素。第三部分:女性性激素依赖性肺癌的筛选因素目的:通过抗性激素治疗效果作为判断女性性激素依赖性肺癌的依据,探讨其与患者一般情况及病理学因素之间的相互关系,筛选女性非小细胞肺癌性激素依赖性患者的影响因素。方法:2007年8月至2014年8月中山大学附属江门医院治疗的女性非小细胞肺癌患者,肿瘤进展后给予他昔莫芬治疗,如果有效判定为性激素依赖性肺癌入A组(29例);进展后给予他昔莫芬治疗无效或加重,判定为肿瘤非依赖性肺癌入B组(83例),单因素分析筛选出与女性性激素依赖性肺癌相关因素后,Logistic回归分析进一步筛选判断。结果:女性性激依赖性肺癌与患者年龄、肿瘤分化程度、经期时间、吸烟状况、初潮年龄、月经周期差异无统计学意义(p0.05),肿瘤类型、婚姻状况、雌激素受体表达、是否绝经、生产次数与女性性激依赖性肺癌差异有统计学意义(p0.05)。采用多因素Logistic回归模型分析,结果示肿瘤类型、婚姻状况、雌激素受体表达、是否绝经、生产次数与女性性激依赖性肺癌差异有统计学意义(P0.05)。结论:肿瘤类型特别是腺癌、婚姻状况、雌激素受体β表达、是否绝经、生产次数可能是女性性激素依赖性肺癌的筛选因素。第四部分:si RNA介导ERβ基因沉默对ERβ高表达的LTEP-a2细胞凋亡的影响目的:研究si RNA(Small Interference RNA)介导ERβ基因沉默对ERβ高表达的的LTEP-a2培养细胞凋亡作用及其对17-β雌二醇敏感性。方法:合成针对ERβ的si RNA,对生长期培养的ERβ高表达的的LTEP-a2细胞进行转染,对比阴性对照组和空白对照组;RT-PCR检测ERβm RNA的表达,Western blot法检测ERβ蛋白的表达。噻唑蓝比色法(MTT法)检测17-β雌二醇培养的转染细胞的存活情况,确定IC50,流式细胞仪检测培养的转染的肺癌细胞的凋亡。结果:1.转染si RNA组ERβm RNA表达明显低于阴性对照组及空白对照组(PO.05)。阴性对照组及空白对照组比较差异无统计学意义(P0.05)。2.转染si RNA组ERβ蛋白表达低于阴性对照组及空白对照组(PO.05)。阴性对照组和空白对照组比较差异无统计学意义(P0.05)3.噻唑蓝比色法(MTT法)结果表明不同浓度的17-β雌二醇干预后,ERβ-si RNA转染组细胞与阴性对照组及空白对照组相比存活率出现显著下降。(PO.05),雌二醇干预对LTEP-a2细胞生长与阴性对照组及空白对照组相比,转染组生长明显抑制(PO.05)4.转染si RNA组在雌二醇干预后LTEP-a2细胞的凋亡率显著增加,转染组与阴性对照组与空白对照组比较,差异有显著性(35.68±1.58%,3.55±0.33%,2.34±0.58%,PO.05)。结论:1.si RNA介导的ERβ基因沉默可以抑制雌激素药物干预后肺癌细胞的增殖。2.si RNA介导的ERβ基因沉默可以增加雌激素药物干预后肺癌细胞的凋亡。3.ERβ-si RNA可能为性激素依赖型肺癌治疗的新的靶点。4.ERβ可能在筛选女性性激素依赖型肺癌非小细胞肺癌中发挥重要作用并且对这些肺癌加以鉴定,为此类肺癌综合治疗提供帮助。
[Abstract]:Non small cell lung cancer has high incidence and high mortality in both male and female tumors. In recent years, the incidence of male lung cancer patients reached a platform stage. The incidence of female lung cancer increased year by year in.2014 year national tumor registration center, which showed that 189 thousand and 600 of the new cases of lung cancer in China in 2010 were women. Second of the second malignant tumors, which account for women's new malignant tumors, are young and have a high incidence. Most of these women have no history of smoking and more adenocarcinoma. Although the incidence of lung cancer in women is increased, some of the studies are due to the increase in female smokers, female cooking fumes or passive smoking, women. The susceptibility to smog, the infection of human papillomavirus (HPV), or the increasing pressure on the life of women in modern society. However, some literature studies have not been found. It is not to be ignored that the effects of smoke on lung cancer are mainly manifested in squamous cell carcinoma. The increase and younger of female lung cancer based on adenocarcinoma is difficult to explain. Gender differences affect the occurrence of non small cell lung cancer, disease progression and different molecular biology, and determine the therapeutic effect and prognosis. The biggest difference between men and women is sex hormone. The most important hormone in sex hormone is estrogen. Estrogen (Estrogen) is a steroid steroid hormone, and there are three kinds of estrogen in human body: Female Estradiol, estradiol and estrone. Female estradiol is the most active. Female estrogen is mainly secreted by ovarian follicles, a small amount is produced by the placenta after pregnancy and has a high affinity with estrogen receptor. In postmenopausal women, the ovaries no longer produce estrogen, and the level of serum estradiol drops significantly. The study shows that estrogen is in body. The proliferation of tumor cells can be induced in both internal and external tests. Progesterone is followed by progestin, progestin is also a female steroid hormone, progestin produced by the corpus luteum of the ovary is progesterone. LH is a glycoprotein hormone secreted by the basophilic cell of the anterior pituitary, mainly promoting the ovary. Ovulation, under the synergistic effect of FSH, forms the corpus luteum and secretes progesterone. Follicle stimulating hormone (FSH) is a glycoprotein hormone secreted by the basophil of the anterior pituitary. Its main function is to promote ovarian follicle development and maturation. The main function of the ovary is to induce the endometrium to change from the proliferating stage to the secretory phase. Hormone receptor (ER) and progesterone receptor (PR) are associated with breast cancer and endometrial cancer. The status of estrogen and progesterone receptor in breast cancer is an important basis for judging the prognosis of breast cancer and endometrial cancer and giving hormone therapy. A significant effect has been achieved to improve the prognosis of breast and endometrial cancer patients. Therefore, it is known as sex hormone dependent tumor for breast cancer and other dependent hormone target organs. Not only that, there is sex hormone receptor in the tumor tissues of the non sex hormone target organs. Previous studies have shown that the lung tissues of normal and lung cancer patients are all stored in the lung tissue. In sex hormone receptors, the level of sex hormone receptors in lung cancer tissues is significantly higher than that of normal people. Lung cancer is also a sex hormone dependent tumor. There are two subtypes of estrogen receptors, estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta). In the previous study, the expression of ER alpha in lung cancer is still controversial, but most of them think that ER alpha is in lung cancer. The main expression of ER beta.ER beta in lung cancer plays an important role in the development of lung cancer, especially in sex as a factor dependent hormone dependent tumor. The mechanism of estrogen and its receptor in tumor may be after the entry of estrogen to the tumor cytoplasm and specific receptor junction. Corticosteroid receptor complex. Hormone receptor complex can pass through the nuclear membrane, enter the nucleus, combine with the receptor in the nucleus and dimerization. It affects the transcription of the nuclear DNA (DNA) in the nucleus, syntheses the new protein, and forms a new tumor. Although anti estrogen therapy has achieved good in vitro or in animal experiments. Good results. However, most of the women with lung cancer are given resistant hormone therapy, and they do not have a better effect and longer survival time. This becomes a lack of targeted anti estrogen therapy. It may be the diagnosis and screening of patients with sex hormone dependent lung cancer that affect the treatment of this type of patients. ER beta may be an important factor in sexual hormone dependent lung cancer. The increase of estrogen before menopause and the decrease of progesterone after menopause may also be an important factor in sex hormone dependent lung cancer. The construction and construction of Si RNA for ER beta may be an important factor in the development of lung cancer. Corresponding vector, transfection of ER beta highly expressed cell line LTEP-a2 in growth period, contrast negative control group and blank control group; RT-PCR detection of ER beta m RNA expression, Western blot method to detect the expression of ER beta protein. Thiazolazole colorimetric assay (MTT method) for detecting the growth of cells transfected by estrogen culture, flow cytometry The apoptosis of the transfected lung cancer cells was detected. In the test in vitro, it was confirmed that ER beta may be an important factor in sex hormone dependent lung cancer. Factors affecting sex hormone dependent patients with small cell lung cancer. Single factor analysis screened the factors associated with sex hormone dependent lung cancer in women. Logistic regression analysis was used to further screen and judge. The development of lung cancer is a complex process. Sex hormone dependent female lung cancer is also a new topic. The study of body and its related mechanisms helps to realize individualized diagnosis and treatment of lung cancer. This study attempts to find the screening conditions for such patients from different aspects and provide a new treatment for non small cell lung cancer in women. This study includes the following four chapters: the estrogen receptor of women with non-small cell lung cancer. Expression and clinical significance Objective: to detect the expression of estrogen receptor in female non-small cell lung cancer patients, to study the relationship with pathological factors and postoperative survival rate, and to explore the clinical value of estrogen receptor expression in female non-small cell lung cancer patients. Methods: the use of immunohistochemical method was used to detect the city center of Jiangmen from March 2007 to 05 months of 2012. The expression of estrogen receptor ER alpha and ER beta, progesterone receptor A (PRA) and progesterone receptor (PRB) in the tumor specimens of 125 patients with non-small cell lung cancer operated by hospital operation, and the comparison of the survival rate of the influencing factors.Kaplan-Meier survival curve. Results: 0 cases of non small cell lung cancer patients were positive for ER alpha, and all tumor cells of lung cancer did not find ER alpha Yang. There were 58 cases of ER beta positive in non small cell lung cancer patients in sex.125. The positive rate was PRA positive in 46.4%.2.125 cases of non small cell lung cancer and 0 cases of PRB positive. All lung cancer cells did not find PRA positive and PRB positive.3.ER beta positive expression and age size, premenopausal status, pathological type of lung cancer and staging, among which the positive rate of adenocarcinoma was the highest, scales were the highest, scales were the highest, scales were the highest, scales of squamous cell carcinoma. The positive rate of cancer was the lowest. The positive expression of ER beta was higher (P0.05), the positive expression of.ER beta and tumor size, the degree of differentiation, and the non smoking history had no significant difference (P0.05) the survival rate of ER beta negative patients before menopause was significantly higher than that of pre menopause ER beta positive female non small cell carcinoma (P0.05), and the positive rate of ER? Positive after menopause was significantly higher than that of menopause. Post female non small cell lung cancer (P0.05). Conclusion: 1. it is important to detect the expression of estrogen receptor in female non small cell lung cancer patients. It can help to understand the postoperative survival of female patients and provide comprehensive treatment for postoperative comprehensive treatment of the patients with.2. tumor tissue, the level of estrogen receptor ER beta can affect the non small cell lung of women. Cancer growth and postoperative survival may be an important factor in the screening of female sex hormone dependent non-small cell lung cancer. The second part: the relationship between the levels of peripheral blood hormone and the expression of estrogen receptor in cancerous tissues in women with non-small cell lung cancer: the trend of increasing and young growth in female non-small cell lung cancer patients, and the study of lung Cancer is also a sex hormone dependent tumor, and sex hormone plays an important role in the development of female non-small cell lung cancer. The study of estrogen receptor beta expression and peripheral blood hormone levels in the cancer tissues of women with non-small cell lung cancer and its clinical significance. Methods: immunoenzyme immunoassay for detection of 2 From March 006 to 05 months, 94 cases of premenopausal and 128 postmenopausal women with non small cell lung cancer were operated in the Jiangmen hospital, Zhongshan University, and 128 cases of postmenopausal women with non small cell lung cancer were peripheral blood hormone estradiol (E2), follicular hormone (FSH), luteinizing hormone (LH), progesterone (P) level. The expression of estrogen receptor ER beta in tumor specimens was detected by immunization after operation. Results: 1. the positive rate of ER beta expression in 94 non small cell lung cancer patients before menopause was 36, the positive rate was 38.29%, and the positive rate of ER beta expression was 47 in 128 cases of non small cell lung cancer patients after menopause, the positive rate of all female patients with 36.72%.2 was negative for progesterone receptor PRA and PRB, the positive rate was 0.3. premenopausal women non small cells. There was no obvious expression of ER beta in 79 patients with normal serum E2 in patients with lung cancer, 25 cases of grade expression, 4 cases of ER beta in 15 patients in the elevated group and 11 cases of grade expression. The expression of estrogen receptor beta between the normal group of E2 and the elevated group in pre menopausal women with non-small cell lung cancer was statistically significant (P0.05).4. premenopausal women were not small There was no difference in the expression of estrogen receptor in serum FSH, LH normal group and elevated group in the patients with cell lung cancer. There was no difference in the expression of estrogen receptor in the normal group of serum P and the lower group (P0.05). There were no obvious expression of ER beta in 75 cases of the normal group of non small cell lung cancer of postmenopausal women with non small cell lung cancer, 32 cases of ER beta, and 6 cases of ER beta in the 21 patients in the lower group. The expression of estrogen receptor in P normal group and lower group of non small cell lung cancer patients in postmenopausal women with non small cell lung cancer was statistically significant (P0.05).6 postmenopausal women with non small cell lung cancer serum E2, FSH, LH normal group and elevated group of estrogen receptor expression were not different. (P0.05). Conclusion: 1. female non small cell lung cancer patients (P0.05). (P0.05). (P0.05). Conclusion: Patients with non small cell lung cancer (P0.05). (P0.05). (P0.05). Conclusion: Patients with non small cell lung cancer (P0.05). (P0.05). (P0.05). Conclusion: the patients with non small cell lung cancer (P0.05). The disorder and imbalance of sex hormone metabolism in peripheral blood.2. premenopausal estrogen may affect the expression of estrogen receptor. Postmenopausal hormone abnormal progestin may affect the expression of estrogen receptor.3. in premenopausal or late menopause, the changes of LH and FSH hormones and there is no difference in the expression of estrogen receptor in the tumor.4. before menopause. Both high influence and postmenopausal progesterone decrease can affect the expression of estrogen receptor and may be an influential factor in sex hormone dependent lung cancer. The third part: screening factors for sex hormone dependent lung cancer in women: the basis for judging female sex induced lung cancer by the effect of resistant hormone therapy, and discuss it with the patients. The relationship between the pathological and pathological factors and the screening of factors affecting sex hormone dependent patients with non small cell lung cancer. Methods: from August 2007 to August 2014, women with non small cell lung cancer, affiliated to the Jiangmen hospital in Zhongshan University, were treated with celecoxifen after the tumor was progressed, if the sex hormone dependence was effectively judged. Lung cancer was admitted into group A (29 cases); the treatment was ineffective or aggravated after the treatment, and it was judged to be a tumor non dependent lung cancer in group B (83 cases). Single factor analysis screened the factors associated with sex hormone dependent lung cancer. Logistic regression analysis was used to further screen and judge. Results: female sex induced lung cancer and patient age, tumor differentiation process There was no significant difference in duration, duration of smoking, smoking status, menarche age and menstrual cycle (P0.05), tumor type, marital status, and estrogen intake.
【学位授予单位】：暨南大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R734.2
本文编号：2126234
[Abstract]:Non small cell lung cancer has high incidence and high mortality in both male and female tumors. In recent years, the incidence of male lung cancer patients reached a platform stage. The incidence of female lung cancer increased year by year in.2014 year national tumor registration center, which showed that 189 thousand and 600 of the new cases of lung cancer in China in 2010 were women. Second of the second malignant tumors, which account for women's new malignant tumors, are young and have a high incidence. Most of these women have no history of smoking and more adenocarcinoma. Although the incidence of lung cancer in women is increased, some of the studies are due to the increase in female smokers, female cooking fumes or passive smoking, women. The susceptibility to smog, the infection of human papillomavirus (HPV), or the increasing pressure on the life of women in modern society. However, some literature studies have not been found. It is not to be ignored that the effects of smoke on lung cancer are mainly manifested in squamous cell carcinoma. The increase and younger of female lung cancer based on adenocarcinoma is difficult to explain. Gender differences affect the occurrence of non small cell lung cancer, disease progression and different molecular biology, and determine the therapeutic effect and prognosis. The biggest difference between men and women is sex hormone. The most important hormone in sex hormone is estrogen. Estrogen (Estrogen) is a steroid steroid hormone, and there are three kinds of estrogen in human body: Female Estradiol, estradiol and estrone. Female estradiol is the most active. Female estrogen is mainly secreted by ovarian follicles, a small amount is produced by the placenta after pregnancy and has a high affinity with estrogen receptor. In postmenopausal women, the ovaries no longer produce estrogen, and the level of serum estradiol drops significantly. The study shows that estrogen is in body. The proliferation of tumor cells can be induced in both internal and external tests. Progesterone is followed by progestin, progestin is also a female steroid hormone, progestin produced by the corpus luteum of the ovary is progesterone. LH is a glycoprotein hormone secreted by the basophilic cell of the anterior pituitary, mainly promoting the ovary. Ovulation, under the synergistic effect of FSH, forms the corpus luteum and secretes progesterone. Follicle stimulating hormone (FSH) is a glycoprotein hormone secreted by the basophil of the anterior pituitary. Its main function is to promote ovarian follicle development and maturation. The main function of the ovary is to induce the endometrium to change from the proliferating stage to the secretory phase. Hormone receptor (ER) and progesterone receptor (PR) are associated with breast cancer and endometrial cancer. The status of estrogen and progesterone receptor in breast cancer is an important basis for judging the prognosis of breast cancer and endometrial cancer and giving hormone therapy. A significant effect has been achieved to improve the prognosis of breast and endometrial cancer patients. Therefore, it is known as sex hormone dependent tumor for breast cancer and other dependent hormone target organs. Not only that, there is sex hormone receptor in the tumor tissues of the non sex hormone target organs. Previous studies have shown that the lung tissues of normal and lung cancer patients are all stored in the lung tissue. In sex hormone receptors, the level of sex hormone receptors in lung cancer tissues is significantly higher than that of normal people. Lung cancer is also a sex hormone dependent tumor. There are two subtypes of estrogen receptors, estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta). In the previous study, the expression of ER alpha in lung cancer is still controversial, but most of them think that ER alpha is in lung cancer. The main expression of ER beta.ER beta in lung cancer plays an important role in the development of lung cancer, especially in sex as a factor dependent hormone dependent tumor. The mechanism of estrogen and its receptor in tumor may be after the entry of estrogen to the tumor cytoplasm and specific receptor junction. Corticosteroid receptor complex. Hormone receptor complex can pass through the nuclear membrane, enter the nucleus, combine with the receptor in the nucleus and dimerization. It affects the transcription of the nuclear DNA (DNA) in the nucleus, syntheses the new protein, and forms a new tumor. Although anti estrogen therapy has achieved good in vitro or in animal experiments. Good results. However, most of the women with lung cancer are given resistant hormone therapy, and they do not have a better effect and longer survival time. This becomes a lack of targeted anti estrogen therapy. It may be the diagnosis and screening of patients with sex hormone dependent lung cancer that affect the treatment of this type of patients. ER beta may be an important factor in sexual hormone dependent lung cancer. The increase of estrogen before menopause and the decrease of progesterone after menopause may also be an important factor in sex hormone dependent lung cancer. The construction and construction of Si RNA for ER beta may be an important factor in the development of lung cancer. Corresponding vector, transfection of ER beta highly expressed cell line LTEP-a2 in growth period, contrast negative control group and blank control group; RT-PCR detection of ER beta m RNA expression, Western blot method to detect the expression of ER beta protein. Thiazolazole colorimetric assay (MTT method) for detecting the growth of cells transfected by estrogen culture, flow cytometry The apoptosis of the transfected lung cancer cells was detected. In the test in vitro, it was confirmed that ER beta may be an important factor in sex hormone dependent lung cancer. Factors affecting sex hormone dependent patients with small cell lung cancer. Single factor analysis screened the factors associated with sex hormone dependent lung cancer in women. Logistic regression analysis was used to further screen and judge. The development of lung cancer is a complex process. Sex hormone dependent female lung cancer is also a new topic. The study of body and its related mechanisms helps to realize individualized diagnosis and treatment of lung cancer. This study attempts to find the screening conditions for such patients from different aspects and provide a new treatment for non small cell lung cancer in women. This study includes the following four chapters: the estrogen receptor of women with non-small cell lung cancer. Expression and clinical significance Objective: to detect the expression of estrogen receptor in female non-small cell lung cancer patients, to study the relationship with pathological factors and postoperative survival rate, and to explore the clinical value of estrogen receptor expression in female non-small cell lung cancer patients. Methods: the use of immunohistochemical method was used to detect the city center of Jiangmen from March 2007 to 05 months of 2012. The expression of estrogen receptor ER alpha and ER beta, progesterone receptor A (PRA) and progesterone receptor (PRB) in the tumor specimens of 125 patients with non-small cell lung cancer operated by hospital operation, and the comparison of the survival rate of the influencing factors.Kaplan-Meier survival curve. Results: 0 cases of non small cell lung cancer patients were positive for ER alpha, and all tumor cells of lung cancer did not find ER alpha Yang. There were 58 cases of ER beta positive in non small cell lung cancer patients in sex.125. The positive rate was PRA positive in 46.4%.2.125 cases of non small cell lung cancer and 0 cases of PRB positive. All lung cancer cells did not find PRA positive and PRB positive.3.ER beta positive expression and age size, premenopausal status, pathological type of lung cancer and staging, among which the positive rate of adenocarcinoma was the highest, scales were the highest, scales were the highest, scales were the highest, scales of squamous cell carcinoma. The positive rate of cancer was the lowest. The positive expression of ER beta was higher (P0.05), the positive expression of.ER beta and tumor size, the degree of differentiation, and the non smoking history had no significant difference (P0.05) the survival rate of ER beta negative patients before menopause was significantly higher than that of pre menopause ER beta positive female non small cell carcinoma (P0.05), and the positive rate of ER? Positive after menopause was significantly higher than that of menopause. Post female non small cell lung cancer (P0.05). Conclusion: 1. it is important to detect the expression of estrogen receptor in female non small cell lung cancer patients. It can help to understand the postoperative survival of female patients and provide comprehensive treatment for postoperative comprehensive treatment of the patients with.2. tumor tissue, the level of estrogen receptor ER beta can affect the non small cell lung of women. Cancer growth and postoperative survival may be an important factor in the screening of female sex hormone dependent non-small cell lung cancer. The second part: the relationship between the levels of peripheral blood hormone and the expression of estrogen receptor in cancerous tissues in women with non-small cell lung cancer: the trend of increasing and young growth in female non-small cell lung cancer patients, and the study of lung Cancer is also a sex hormone dependent tumor, and sex hormone plays an important role in the development of female non-small cell lung cancer. The study of estrogen receptor beta expression and peripheral blood hormone levels in the cancer tissues of women with non-small cell lung cancer and its clinical significance. Methods: immunoenzyme immunoassay for detection of 2 From March 006 to 05 months, 94 cases of premenopausal and 128 postmenopausal women with non small cell lung cancer were operated in the Jiangmen hospital, Zhongshan University, and 128 cases of postmenopausal women with non small cell lung cancer were peripheral blood hormone estradiol (E2), follicular hormone (FSH), luteinizing hormone (LH), progesterone (P) level. The expression of estrogen receptor ER beta in tumor specimens was detected by immunization after operation. Results: 1. the positive rate of ER beta expression in 94 non small cell lung cancer patients before menopause was 36, the positive rate was 38.29%, and the positive rate of ER beta expression was 47 in 128 cases of non small cell lung cancer patients after menopause, the positive rate of all female patients with 36.72%.2 was negative for progesterone receptor PRA and PRB, the positive rate was 0.3. premenopausal women non small cells. There was no obvious expression of ER beta in 79 patients with normal serum E2 in patients with lung cancer, 25 cases of grade expression, 4 cases of ER beta in 15 patients in the elevated group and 11 cases of grade expression. The expression of estrogen receptor beta between the normal group of E2 and the elevated group in pre menopausal women with non-small cell lung cancer was statistically significant (P0.05).4. premenopausal women were not small There was no difference in the expression of estrogen receptor in serum FSH, LH normal group and elevated group in the patients with cell lung cancer. There was no difference in the expression of estrogen receptor in the normal group of serum P and the lower group (P0.05). There were no obvious expression of ER beta in 75 cases of the normal group of non small cell lung cancer of postmenopausal women with non small cell lung cancer, 32 cases of ER beta, and 6 cases of ER beta in the 21 patients in the lower group. The expression of estrogen receptor in P normal group and lower group of non small cell lung cancer patients in postmenopausal women with non small cell lung cancer was statistically significant (P0.05).6 postmenopausal women with non small cell lung cancer serum E2, FSH, LH normal group and elevated group of estrogen receptor expression were not different. (P0.05). Conclusion: 1. female non small cell lung cancer patients (P0.05). (P0.05). (P0.05). Conclusion: Patients with non small cell lung cancer (P0.05). (P0.05). (P0.05). Conclusion: Patients with non small cell lung cancer (P0.05). (P0.05). (P0.05). Conclusion: the patients with non small cell lung cancer (P0.05). The disorder and imbalance of sex hormone metabolism in peripheral blood.2. premenopausal estrogen may affect the expression of estrogen receptor. Postmenopausal hormone abnormal progestin may affect the expression of estrogen receptor.3. in premenopausal or late menopause, the changes of LH and FSH hormones and there is no difference in the expression of estrogen receptor in the tumor.4. before menopause. Both high influence and postmenopausal progesterone decrease can affect the expression of estrogen receptor and may be an influential factor in sex hormone dependent lung cancer. The third part: screening factors for sex hormone dependent lung cancer in women: the basis for judging female sex induced lung cancer by the effect of resistant hormone therapy, and discuss it with the patients. The relationship between the pathological and pathological factors and the screening of factors affecting sex hormone dependent patients with non small cell lung cancer. Methods: from August 2007 to August 2014, women with non small cell lung cancer, affiliated to the Jiangmen hospital in Zhongshan University, were treated with celecoxifen after the tumor was progressed, if the sex hormone dependence was effectively judged. Lung cancer was admitted into group A (29 cases); the treatment was ineffective or aggravated after the treatment, and it was judged to be a tumor non dependent lung cancer in group B (83 cases). Single factor analysis screened the factors associated with sex hormone dependent lung cancer. Logistic regression analysis was used to further screen and judge. Results: female sex induced lung cancer and patient age, tumor differentiation process There was no significant difference in duration, duration of smoking, smoking status, menarche age and menstrual cycle (P0.05), tumor type, marital status, and estrogen intake.
【学位授予单位】：暨南大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R734.2
【相似文献】
相关期刊论文 前10条
1 郝瑞芳;;中西医结合治疗儿童激素依赖性原发性肾病综合征27例[J];中国中医药信息杂志;2007年07期
2 陈晓风;;中药治疗激素依赖性原发性肾病综合征29例[J];中医杂志;2007年11期
3 边艳玲;;北京林江涛主任治好了我的激素依赖性哮喘[J];求医问药;2013年05期
4 李海波;;80例面部激素依赖性皮炎患者治疗分析[J];中国现代药物应用;2008年12期
5 王洁,叶任高;中西医结合治疗成人激素依赖性原发性肾病综合征40例疗效观察[J];中国中西医结合肾病杂志;2003年11期
6 魏连波,卢元元,叶任高,栾图;中西医结合治疗成人激素依赖性原发性肾病综合征临床观察[J];南京中医药大学学报(自然科学版);2000年04期
7 孙蔚凌;范卫新;闵仲生;王飞;蒋艺;马慧军;张莉;李珊山;田亚平;杨卫兵;岳学状;;蓝科肤宁治疗面部激素依赖性皮炎疗效观察[J];临床皮肤科杂志;2008年04期
8 李平;;用抗黄体激素治疗激素依赖性乳腺癌[J];国外医学情报;1991年14期
9 罗星照;;特发性肾病综合征的环磷酰胺疗法[J];国外医学参考资料(内科学分册);1977年12期
10 赵庆利,王毅侠,史飞,冯燕君,吴卫红;三种方法治疗面部激素依赖性皮炎疗效比较[J];中国皮肤性病学杂志;2004年02期
相关会议论文 前10条
1 潘海英;盛丽先;;激素依赖性肾病患儿皮质醇水平临床观察[A];第七届全国中西医结合肾脏病会议论文汇编[C];2003年
2 吴红;邵敬於;林敏;;国产醋酸亮丙瑞林缓释微球注射剂治疗性激素依赖性疾病(附6例妊娠报道)[A];2005年上海市生物医学工程学会学术年会论文集[C];2005年
3 王和平;潘仁泉;冯国歌;;喘可治注射液与舒利碟和ACTH联合疗法治疗激素依赖性哮喘10例[A];中华医学会第二次全国变态反应学术会议论文汇编[C];2004年
4 王和平;张秋兴;;喘可治注射液与舒利迭和ACTH联合疗法治疗激素依赖性哮喘10例[A];中华医学会第二次全国变态反应学术会议论文汇编[C];2004年
5 张新民;唐蜜;李代强;;磷酸化酪氨酸蛋白在非小细胞肺癌中的表达及其意义[A];中华医学会病理学分会2006年学术年会论文汇编[C];2006年
6 胡旭东;杨国仁;霍宗伟;方永存;陈鸣陆;;~(99m)Tc-MIBI SPECT显像观察非小细胞肺癌多药耐药的研究[A];首届全国肿瘤核医学新技术研讨会论文集[C];2007年
7 秦庆亮;熊海健;王爱;边海蓉;卢振国;杨培英;朱斌耀;王芸;;立体定向放射治疗放疗后复发非小细胞肺癌[A];2007第六届全国放射肿瘤学学术年会论文集[C];2007年
8 冯耘;万欢英;高蓓莉;项轶;刘嘉琳;;血管紧张素转换酶二在非小细胞肺癌肿瘤生长和血管生成中的作用[A];中华医学会第五届全国胸部肿瘤及内窥镜学术会议论文汇编[C];2011年
9 ;非小细胞肺癌术后辅助治疗及一线治疗[A];天津市抗癌协会肺癌专业委员会2011年学术年会论文集[C];2011年
10 蒋峰;许林;史美祺;;1560例非小细胞肺癌患者多因素预后分析[A];第13届全国肺癌学术大会论文汇编[C];2013年
相关重要报纸文章 前10条
1 主治医师 韩咏霞;出现激素依赖性哮喘怎么办[N];中国医药报;2002年
2 杨硕 武维屏 崔红生;北京中医药大学明确：激素依赖性哮喘因机证治[N];中国医药报;2005年
3 武维屏;激素依赖性哮喘的中医治疗[N];中国中医药报;2004年
4 海 霞;中医药治疗激素依赖性哮喘有优势[N];中国中医药报;2004年
5 记者 李颖;特罗凯对中国非小细胞肺癌患者效果佳[N];科技日报;2007年
6 晓白;非小细胞肺癌研究获重大进展[N];人民日报;2008年
7 记者 张文天;非小细胞肺癌中医药综合医疗方案研究进展顺利[N];科技日报;2009年
8 辛勇 张先稳;早期非小细胞肺癌的治疗进展[N];中国中医药报;2004年
9 记者高新军;专家提出 建非小细胞肺癌中医临床指南[N];中国中医药报;2009年
10 上海长海医院呼吸科 夏阳 整理 邱志涛;非小细胞肺癌放虎归山还是乘胜追击[N];健康报;2013年
相关博士学位论文 前10条
1 卢珠明;性激素依赖性肺癌女性患者的筛选及其临床意义[D];暨南大学;2017年
2 白艳（Bai Sally）;整合素αvβ5合并EGFR检测用于非小细胞肺癌转移及预后评估的研究[D];复旦大学;2013年
3 王筱恬;PLZF和DACH1的异常表达影响非小细胞肺癌发生与发展的分子机制[D];复旦大学;2012年
4 洪专;木犀草素治疗EGF受体继发性突变的非小细胞肺癌的实验研究[D];南京大学;2014年
5 张沛;ILT4在非小细胞肺癌中的作用及分子机制研究[D];山东大学;2015年
6 王世坤;RBP2诱导非小细胞肺癌和食管鳞癌表皮间质化[D];山东大学;2015年
7 赵世俊;~(18)F-FDG PET/CT在非小细胞肺癌预后评估中的应用研究[D];北京协和医学院;2013年
8 邱晨;影响非小细胞肺癌手术后远期生存的相关因素分析[D];山东大学;2015年
9 姜远瞩;术前血液学指标与淋巴结转移阴性非小细胞肺癌患者预后关系的研究[D];山东大学;2015年
10 朱良明;STAT3及其靶基因对非小细胞肺癌生物学行为调控机制的初步实验研究[D];山东大学;2015年
相关硕士学位论文 前10条
1 郭德阳;芳香化酶抑制剂用于绝经后激素依赖性乳腺癌患者新辅助内分泌治疗效果的Meta分析[D];重庆医科大学;2016年
2 务改艳;乳癌方对激素依赖性乳腺癌患者卵巢功能的干预研究[D];广州中医药大学;2016年
3 王青青;怡癜饮治疗激素依赖性免疫性血小板减少症的临床研究[D];广州中医药大学;2013年
4 陈瑶;激素依赖性特发性血小板减少性紫癜中医证型分布规律研究[D];广州中医药大学;2011年
5 曹鸿舜;寇辉教授运用引火归原法治疗激素依赖性哮喘经验浅析[D];辽宁中医药大学;2012年
6 王勇;诱导型一氧化氮合酶在非小细胞肺癌中表达的临床意义[D];中国医科大学;2006年
7 陈婷;非小细胞肺癌调强放射治疗预后因素分析[D];福建医科大学;2015年
8 王波;单向式全胸腔镜下解剖性肺叶切除术治疗早期非小细胞肺癌的学习曲线[D];福建医科大学;2015年
9 施桂清;血管内皮抑制素联合放化疗治疗非小细胞肺癌的疗效及安全性研究[D];福建医科大学;2015年
10 王静;Eg5、Ki-67在非小细胞肺癌中的表达及临床意义[D];河北医科大学;2015年
，本文编号：2126234
本文链接：https://www.wllwen.com/yixuelunwen/zlx/2126234.html
