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Thyroid cancer detection significance of Bcl-2
[Abstract] Objective To investigate the expression of Bcl-2 in the
incidence of thyroid cancer, development and immunohistochemical methods, mouse anti-human monoclonal antibodies to Bcl-2 mark 77 cases of thyroid cancer, 58 cases of thyroid 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 positive rate was %, higher than the thyroid adenoma %) (P = , adjacent thyroid tissue %) (P = and normal thyroid Organizations (0) (P = . anaplastic thyroid carcinoma and follicular carcinoma of the Bcl-2 positive rate was significantly higher. presence lymph node metastasis and clinical stage Ⅲ, Ⅳ 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 Cancer, Bcl-2 Gene, Proto-Oncogenes, Gene Expression, Immunohistochemistry
Thyroid 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 carcinoma 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 quickly. 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 adenoma, 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 Methods
Materials
All specimens were obtained 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 adjacent 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 according 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, Ⅱ 23 cases, Ⅲ of 16 cases, Ⅳ of eight cases, of which 33 patients with lymph node metastasis, no lymph node metastasis in 44 cases. specimens were fixed in 10% formalin solution, embedded in paraffin buried, routine biopsy, 60 ℃ baking sheet 2 h, 37 ℃ overnight reserve.
Immunohistochemistry Reagents
Bcl-2 mouse anti-human monoclonal antibody, for the United States ZYMED company's products.SP-9000 Universal kit . ZYMED Company. Using known
Bcl-2-positive tonsil as a positive control, with PBS instead of primary antibody as negative space controls.
Test Methods
Dewaxing hydration, 3% H2O2 treatment at room temperature 15 min, microwave antigen retrieval, normal goat serum incubated 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.
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, the results are inconsistent harmonization judge the final result.
Statistical Analysis
All data using SPSS statistical package on a computer for statistical analysis, for χ.2 test to P ≤ was considered statistically
significant.
2 Results
Bcl-2 In Different Tissues Of The Thyroid 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 %, higher than the thyroid adenoma %) (P ≤ and adjacent thyroid tissue %) (P ≤ , while the normal thyroid tissue were negative. shown in Table 1.
thyroid cancer Bcl-2 expression and thyroid cancer related pathological parameters, see Table expression levels and histological type of thyroid cancer, lymph node metastasis and clinical staging a significant relationship. 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 Ⅲ, Ⅳ cases, Bcl-2 was higher than the corresponding without lymph node metastasis and
clinical I, Ⅱ stage cases, the di fferences were statistically significant (P <. posted on free download Discussion
Apoptosis, 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 apoptosis, 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 / leukemia 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
follicular 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 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 new 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, preferentially 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 differentiation, 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 expression of Bcl-2 was %, significantly higher than the thyroid adenoma %, P = , thyroid cancer adjacent tissues %, P = and normal thyroid tissue (0, P = , reveals the thyroid follicular cell adenomas bcl-2 positive staining intensity and number of positive cells compared 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 thyroid 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 undifferentiated carcinoma and relatively low follicular carcinoma, Bcl-2 expression rates were 100% and %, significantly higher than papillary carcinoma of Bcl-2 expression rate %), the differences were statistically significant, in patients with lymph node metastasis or III, IV cases of thyroid 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 thyroid 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 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％，高于甲状腺腺瘤组织％)(P=0．006)、癌旁甲状腺组织％)(P=0．003)和正常甲状腺组织(0)(P=0．000)。

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Ⅲ、Ⅳ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瘤，女性发病率高。

临床甲状腺肿瘤中有5％~10％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与甲状腺癌的生物学行为的关系及其预后关系。

1 材料与方法
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，Ⅱ期23例，Ⅲ期16例，Ⅳ期8例；其中，有淋巴结转移者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。

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。

试验方法
切片脱蜡水化后，3％H2O2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。

经苏木精复染后，脱水、透明、封片。

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。

统计学分析
所有数据采用SPSS 统计软件包在电脑上进行统计分析，进行χ.2检验，以P≤为差异有统计学意义。

2 结果
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性。

Bcl-2阳性率在甲状腺癌为％，高于甲状腺腺瘤％)(P≤及癌旁甲状腺组织％)(P≤，而正常甲状腺组织染色阴性。

见表1。

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Ⅲ、Ⅳ期病例，Bcl-2阳性率高于相应的无淋巴结转移和临床I、Ⅱ期病例，差异均有统计学意义(P<。

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，对其研究将是解决细胞凋亡机制的根本。

但迄今为止其确切作用机制仍不完全清楚。

bcl-2基因家族在凋亡的调节中起重要作用，是研究热点之一。

Bcl-2基因即B细胞淋巴瘤/白血病基因-2(B-cell lymphoma/leukemia-2)，是Tsujimoto
等［5］于1984年首次在滤泡型B淋巴瘤中发现，由此命名Bcl-2。

正常位于18号染色体的长臂2区1带，开始是通过染色体易位(14，18)断裂点的分子克隆方法，从滤泡型淋巴细胞瘤中分离出来的，被人们认为是人类滤泡型淋巴细胞瘤的细胞遗传学标志，由2个外显子组成，其基因产物在人类中的表达与细胞寿命长短相关。

近年来，人们通过广泛的研究发现，Bcl-2基因有阻滞细胞凋亡发生的作用，故被认为是抗细胞凋亡基因［6］。

其抑制凋亡的机制，以前报道笼统说通过阻止细胞凋亡信号传输的最后共同通路而起作用。

通过对bcl-2结合蛋白和bcl-2同源蛋白的研究，对bcl-2家族调控凋亡的基本模式有了新的认识。

bcl-2同源蛋白包括bcl-2、bcl-xL、bax、bad以及线虫的ced-9，bcl-2、bax可以以同二聚体形式存在，也可形成异二聚体，bax同源二聚体形成，诱导凋亡，bax--bcl-2异二聚体形成，抑制凋亡；而当bcl-xs存在时，优先与bcl-2形成异二聚体，使bax得以游离形成同二聚体，诱导凋亡，因此，有时bcl-2表达并不一定抑制细胞凋亡的发生。

一般认为，bcl-2基因表达与瘤细胞的分化程度及增殖能力有关，分化程度低，增殖能力强的瘤细胞，其bcl-2呈现出过量表达趋势。

本研究中，作者系统地检测了甲状腺癌组织、甲状腺腺瘤组织、甲状腺癌旁组织及正常甲状腺组织等多种甲状腺组织中Bcl-2的表达情况，显示在甲状腺癌组织Bcl-2的表达率为％，显著高于甲状腺腺瘤组织％，P=、甲状腺癌旁的组织％，P=及正常甲状腺组织(0，P=，揭示出甲状腺腺瘤的滤泡上皮细胞bcl-2阳性染色强度及阳性细胞数较正常甲状腺滤泡上皮细胞增强增多，甲状腺癌又超过腺瘤，提示bcl-2可能在调节甲状腺上皮的凋亡中伴演重要角色，在甲状腺癌中有更多的上皮细胞具有逃避凋亡的能力，甲状腺癌的发生可能与bcl-2过量表达有关。

研究表明，对于甲状腺癌，肿瘤组织学类型、年龄、淋巴结转移情况及临床病理分期是评估预后的主要指标［7、8］。

本组研究结果表明，在分化程度很低的未分化癌和相对较低的滤泡状癌中，Bcl-2的表达率分别为100％与％，明显高于乳头状癌Bcl-2的表达率％)，差异均具有统计学意义；在有淋巴结转移的病例或III、IV期甲状腺癌病例中，癌组织中Bcl-2的表达明显增强，差异均具有统计学意义。

Bcl-2在甲状腺癌所有类型中均有表达，并且分化越差表达程度越高，因此，有理由认为，Bcl-2阳性提示甲状腺癌预后较差，并且表达程度越高预后也就越差。

癌组织Bcl-2高表达与甲状腺癌的分化程度、组织学亚型、增值侵袭能力、淋巴结转移以及预后有关，可作为判断甲状腺癌预后的一个重要参考指标。

因此，对于甲状腺腺瘤患者，作肿瘤组织Bcl-2检测并对阳性病例进行密切随访可能具有重要意义。