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1、Thyroid cancer detection significance of Bcl-2Abstract Objective To investigate the expression of Bcl-2 in the incidence of thyroid cancer, development and prognosis.Methods immunohistochemical methods, mouse anti-human monoclonal antibodies to Bcl-2 mark 77 cases of thyroid cancer, 58 cases of thyr

2、oid adenoma and 40 cases of adjacent thyroid tissue and 28 cases of normal thyroid tissue. observe the different thyroid tissue expression of Bcl-2, and compare the positive rate of Bcl-2 positive results seen in thyroid cancer, thyroid adenoma and adjacent thyroid tissue. in thyroid carcinoma Bcl-2

3、 positive rate was 45.5%, higher than the thyroid adenoma (22.4%) (P = 0.006), adjacent thyroid tissue (17.5%) (P = 0.003) and normal thyroid Organizations (0) (P = 0.000). anaplastic thyroid carcinoma and follicular carcinoma of the Bcl-2 positive rate was significantly higher. presence lymph node

4、metastasis and clinical stage , cases, Bcl-2 positive rate significantly increased. Conclusions Bcl-2 overexpression may be associated with the occurrence of thyroid tumors, cancer tissue expression of Bcl-2 can be used as a reference indicator of thyroid cancer prognosis. Keywords: Thyroid Can

5、cer, Bcl-2 Gene, Proto-Oncogenes, Gene Expression, ImmunohistochemistryThyroid cancer is a common endocrine cancer, women with a high incidence of clinical thyroid tumors in 5% to 10% of thyroid cancer 1 which differentiated thyroid cancer accounts for 90 percent, including papillary thyroid carcino

6、ma and follicular thyroid carcinoma , undifferentiated carcinoma are rare, its high degree of malignancy and poor prognosis. domestic data show that the incidence of thyroid cancer in a significant increase in 2 In recent years, thyroid cancer-related genes and tumor marker studies progressed very q

7、uickly. study confirmed 3,4, Bcl-2 gene is an apoptosis suppressor gene, first discovered in follicular B-cell lymphomas, and its product Bcl-2 protein inhibits apoptosis and prolong cell survival. The Studies using immunohistochemical techniques, by detecting Bcl-2 in thyroid cancer, thyroid adenom

8、a, thyroid cancer tissue and normal thyroid tissue levels of Bcl-2 study in thyroid cancer incidence in the development process role in order to reveal the Bcl-2 and thyroid cancer biological behavior and prognosis of relationships. 1 Materials And Methods1.1 MaterialsAll specimens were obtaine

9、d from Peking University Shenzhen Hospital General Surgery from 2001 to 2009 cases of thyroid surgery between specimens, including: thyroid cancer, 77 cases (28 males and 8 females, mean 50 years), 58 cases of thyroid adenoma (male 22 cases, 36 females, mean 36 years), while taking 40 cases of adjac

10、ent thyroid tissue (10 males and 30 females, with an average 37 years old, had no diagnosed by pathological examination of thyroid cancer invasion), 28 cases of normal thyroid tissue ( 9 males and females l9 cases, mean 35 years). pair of 77 cases of thyroid cancer histological classification accord

11、ing to WHO criteria: 55 cases of papillary carcinoma, follicular carcinoma l4 cases, undifferentiated carcinoma in 8 cases, according to standard clinical AJCC staging : I period of 30 cases, 23 cases, of 16 cases, of eight cases, of which 33 patients with lymph node metastasis, no lymph node metast

12、asis in 44 cases. specimens were fixed in 10% formalin solution, embedded in paraffin buried, routine biopsy, 60 baking sheet 2 h, 37 overnight reserve. 1.2 Immunohistochemistry ReagentsBcl-2 mouse anti-human monoclonal antibody, for the United States ZYMED company's products. SP-9000

13、Universal kit U.S. ZYMED Company. Using known Bcl-2-positive tonsil as a positive control, with PBS instead of primary antibody as negative space controls. 1.3 Test MethodsDewaxing hydration, 3% H2O2 treatment at room temperature 15 min, microwave antigen retrieval, normal goat serum incubated

14、30 min, dropping a resistance, 4 refrigerator overnight incubation. Dropping biotinylated secondary antibody sign incubated at room temperature 30 min, dropping horseradish peroxidase-labeled streptavidin at room temperature 30 min, DAB color. dyed by hematoxylin, dehydrated, transparent, mounted.&#

15、160;1.4 criteria Bcl-2 located in the cell membrane and cytoplasm to the cell membrane and cytoplasm appear yellow to dark yellow granules positive cells without Bcl-2 positive cells was negative, there are positive Bcl-2 positive cells in all specimens are two pathologists blinded read the piece, t

16、he results are inconsistent harmonization judge the final result. 1.5 Statistical AnalysisAll data using SPSS 13.0 statistical package on a computer for statistical analysis, for .2 test to P 0.05 was considered statistically significant. 2 Results2.1 Bcl-2 In Different Tissues Of The Thyr

17、oid Condition, Are Shown In Table 1.Bcl-2 light microscope showed positive reaction cell membrane and cytoplasm stained tan, brown granules seen as negative. Bcl-2 positive rate of thyroid cancer was 45.5%, higher than the thyroid adenoma (22.4%) (P 0.01) and adjacent thyroid tissue (17.5%) (P

18、0.01), while the normal thyroid tissue were negative. shown in Table 1. 2.2 thyroid cancer Bcl-2 expression and thyroid cancer related pathological parameters, see Table 2.Bcl-2 expression levels and histological type of thyroid cancer, lymph node metastasis and clinical staging a significant r

19、elationship. Higher in malignant undifferentiated carcinoma and follicular carcinoma, Bcl-2 were significantly higher than lower grade papillary carcinoma with lymph node metastasis and clinical stage , cases, Bcl-2 was higher than the corresponding without lymph node metastasis and clinical I, stag

20、e cases, the differences were statistically significant (P <0.01). posted on free download 3 DiscussionApoptosis, also known as programmed cell death, regulated by genes, regulatory genes can be divided into apoptosis gene and apoptosis-promoting genes, both of the shift, the regulation of apopto

21、sis, cells of their research will be solved The fundamental mechanism of apoptosis, but its exact mechanism of action is still not so far fully understood. bcl-2 gene family in the regulation of apoptosis plays an important role, is one of the hot. Bcl-2 gene that B-cell lymphoma / leukemi

22、a gene -2 (B-cell lymphoma/leukemia-2), is Tsujimoto, etc. 5 in 1984 for the first time in follicular lymphoma B found thus named Bcl-2. normally located in the long arm of chromosome 18 Zone 2 a band to start is by chromosomal translocation (14,18) breaking point Molecular cloning method, from foll

23、icular lymphoma in the isolated, is believed to be human follicular lymphoma cytogenetics mark by two exons, and its gene product expression in humans cell longevity related to recent years, people discovered through extensive research, Bcl-2 gene block cell apoptosis effect, it is considered to be

24、anti-apoptotic genes 6. their anti-apoptotic mechanisms, previously reported general said by preventing apoptosis signaling the final common pathway and work. Through the bcl-2 and bcl-2 binding protein homologous protein research on the regulation of apoptotic bcl-2 family, the basic model has a ne

25、w understanding. bcl-2 homolog proteins including bcl-2, bcl-xL, bax, bad and nematode ced-9, bcl-2, bax can form homodimers can also form heterodimers, bax homodimer formation, induction of apoptosis, bax - bcl-2 heterodimer formation, inhibition of apoptosis, and when the bcl-xs exists, preferenti

26、ally form heterodimers bcl-2, bax to make free homodimer formation and induce apoptosis, therefore, sometimes bcl-2 expression does not necessarily inhibit cell apoptosis. generally believed, bcl-2 gene expression and tumor cell differentiation and proliferation related to the low degree of differen

27、tiation, proliferative ability of the tumor cells, the bcl-2 overexpression trend showed in this study, the authors systematically examined thyroid cancer, thyroid adenoma, thyroid cancer tissue and normal thyroid tissue and other thyroid tissue Bcl -2 expression, as shown in thyroid cancer tissue e

28、xpression of Bcl-2 was 45.5%, significantly higher than the thyroid adenoma (22.4%, P = 0.006), thyroid cancer adjacent tissues (17.5%, P = 0.003) and normal thyroid tissue (0, P = 0.000), reveals the thyroid follicular cell adenomas bcl-2 positive staining intensity and number of positive cells com

29、pared with normal thyroid follicular epithelial cells enhanced increase in thyroid cancer has more than adenoma, suggesting bcl-2 may regulate thyroid epithelial apoptosis associated with play an important role in thyroid epithelial cells have more ability to evade apoptosis, the incidence of thyroi

30、d cancer may be associated with overexpression of bcl-2 related study showed that For thyroid cancer, tumor histological type, age, lymph node metastasis and clinical staging is to assess the prognostic indicators 7,8 in this group research results show a very low degree of differentiation of undiff

31、erentiated carcinoma and relatively low follicular carcinoma, Bcl-2 expression rates were 100% and 78.6%, significantly higher than papillary carcinoma of Bcl-2 expression rate (29.1%), the differences were statistically significant, in patients with lymph node metastasis or III, IV cases of thyroid

32、 cancer, carcinoma of Bcl-2 expression was significantly increased, the differences were statistically significant. Bcl-2 in all types of thyroid cancer were expressed, and the higher the degree of differentiation of the poorer expression, Therefore, it is reasonable that, Bcl-2-positive prompts thy

33、roid cancer with poor prognosis, and the higher the degree of expression is also worse prognosis. cancer tissue expression of Bcl-2 high degree of differentiation of thyroid cancer, histological subtype, value invasion , lymph node metastasis and prognosis, thyroid cancer prognosis could be used as

34、an important reference. Therefore, thyroid adenoma patients for tumor tissue Bcl-2 positive cases detected and close follow-up may have important significance. 甲状腺肿瘤检测Bcl-2的意义【摘要】 目的 探讨Bcl-2的表达与甲状腺癌的发生、发展及预后的关系。方法 应用免疫组化方法，以单克隆抗体鼠抗人Bcl-2标记77例甲状腺癌、58例甲状腺腺瘤、40例癌旁甲状腺组织和28例正常甲状腺组织。观察不同甲状腺组织中Bcl-2的表

35、达，并比较其阳性率。结果 Bcl-2阳性反应见于甲状腺癌、甲状腺腺瘤及癌旁甲状腺组织。在甲状腺癌组织中Bcl-2阳性率为45.5，高于甲状腺腺瘤组织(22.4)(P=0006)、癌旁甲状腺组织(17.5)(P=0003)和正常甲状腺组织(0)(P=0000)。甲状腺未分化癌和滤泡状癌组织中Bcl-2的阳性率明显增高。存在淋巴结转移和临床、期病例中，Bcl-2的阳性率明显增高。结论 Bcl-2过量表达可能与甲状腺肿瘤的发生有关，癌组织中Bcl-2的表达可作为甲状腺癌预后的参考指标。 【关键词】 甲状腺肿瘤；Bcl-2基因；原癌基因；基因表达；免疫组化 甲状腺癌是常见的内分泌肿

36、瘤，女性发病率高。临床甲状腺肿瘤中有510为甲状腺癌1。其中分化型甲状腺癌占90，包括甲状腺乳头状癌和甲状腺滤泡状癌，未分化癌较为少见，其恶性程度高、预后差。国内资料显示我国甲状腺癌的发病率在明显增加2。近年来，甲状腺癌的相关基因和肿瘤标志物研究进展很快。研究证实3，4，Bcl-2基因是一种细胞凋亡抑制基因，最早发现于滤泡性B细胞性淋巴瘤中，其产物Bcl-2蛋白可抑制细胞凋亡，延长细胞生存期。本研究采用免疫组化技术，通过检测Bcl-2在甲状腺癌组织、甲状腺腺瘤组织、甲状腺癌旁组织及正常甲状腺组织中的表达水平，探讨Bcl-2在甲状腺癌组织中的发生发展过程中的作用，以揭示Bcl-2与甲状腺癌的生物

37、学行为的关系及其预后关系。 1 材料与方法 1.1 材料 全部标本取自北京大学深圳医院普通外科2001年至2009年间手术治疗的甲状腺病例标本，其中：甲状腺癌77例(男28例，女8例，平均50岁)，58例甲状腺腺瘤(男22例，女36例，平均36岁)，同时取癌旁甲状腺组织40例(男10例，女30例，平均37岁，经病理检查确诊均无甲状腺癌浸润)；取正常甲状腺组织28例(男9例，女l9例，平均35岁)。对77例甲状腺癌按WHO标准组织学分类：乳头状癌55例，滤泡状癌l4例，未分化癌8例，按AJCC标准临床病理分期：I期30例，期23例， 期16例，期8例；其中，有淋巴结

38、转移者33例，无淋巴结转移者44例。标本经10 福尔马林液固定、石蜡包埋，常规切片，60烤片2 h，37过夜备用。 1.2 免疫组化试剂 Bcl-2鼠抗人单克隆抗体，为美国ZYMED公司产品。SP-9000通用型试剂盒为美国ZYMED公司产品。用已知Bcl-2阳性的扁桃体作阳性对照，以PBS代替一抗作阴性空白对照。1.3 试验方法 切片脱蜡水化后，3H2O2室温处理15 min，微波抗原修复，正常山羊血清室温孵育30 min，滴加一抗，4冰箱孵育过夜。滴加生物素标志的二抗，室温孵育30 min，滴加辣根过氧化酶标记的链亲和素室温30 min，DAB显色。经苏木精复

39、染后，脱水、透明、封片。 1.4 判断标准 Bcl-2定位于细胞膜及细胞质，以细胞膜及细胞质内出现黄色至深棕黄色颗粒为阳性细胞。无阳性细胞为Bcl-2阴性；有阳性细胞为Bcl-2阳性。所有标本均由两位病理医师采用盲法阅片，结果不一致时协调统一判断最终结果。 1.5 统计学分析 所有数据采用SPSS 13.0统计软件包在电脑上进行统计分析，进行.2检验，以P0.05为差异有统计学意义。 2 结果 2.1 Bcl-2在不同甲状腺组织中的表达情况，见表1。 光镜下Bcl-2阳性反应表现为细胞膜及细胞质染成棕褐色，未见棕褐色颗粒为阴

40、性。Bcl-2阳性率在甲状腺癌为45.5，高于甲状腺腺瘤(22.4)(P0.01)及癌旁甲状腺组织(17.5)(P0.01)，而正常甲状腺组织染色阴性。见表1。 2.2 甲状腺癌中Bcl-2表达与甲状腺癌有关病理指标的关系，见表2。Bcl-2的表达程度与甲状腺癌组织学类型、淋巴结转移情况和临床病理分期有显著关系。在恶性度较高的未分化癌和滤泡状癌中，Bcl-2阳性率明显高于恶性度较低的乳头状癌；在有淋巴结转移病例或临床 、期病例，Bcl-2阳性率高于相应的无淋巴结转移和临床I、期病例，差异均有统计学意义(P<0.01)。 3 讨论 细胞凋亡又称细胞程序化死亡，受基因调控，调控基因大体分为凋亡抑制基因和凋亡促进基因，二者此消彼长，共同调节细胞的凋亡， 对其