STAT3及其靶基因PTTG在垂体腺瘤组织中的表达及意义
发布时间：2018-09-03 18:03
【摘要】：前言垂体腺瘤是颅内常见的良性肿瘤,约占颅内肿瘤的10%～25%。它们起源于高度分化的分泌一种或多种激素的垂体前叶细胞。根据病理类型,垂体腺瘤可以分为生长激素(growth hormone, GH)腺瘤、泌乳素(prolactin, PRL)腺瘤、促肾上腺皮质激素腺瘤(adrenocorticotrophic hormone, ACTH)腺瘤、无功能(nonfunctioning,NF)腺瘤等,不同类型肿瘤临床表现亦不同,例如肢端肥大症、闭经/溢乳、库欣综合征或仅仅表现为压迫周围结构等症状。无论何种病理类型,大多数垂体腺瘤生长缓慢,但少数垂体腺瘤表现为恶性生物学行为,例如侵袭性快速生长,对常规手术、放射、药物治疗无反应等。因此,判断肿瘤生物学行为有助于判断肿瘤预后和治疗。因为目前常规的组织病理学检查不能有效地区别不同垂体腺瘤细胞细微的形态差别和生物学意义。因此,进一步研究垂体腺瘤发生、发展的分子生物学机制,发现肿瘤标志物及其临床意义,对于垂体腺瘤的预防、诊断、预后评价和治疗选择将有重大的意义。Janus蛋白酪氨酸激酶(Janus protein tyrosine kinase, JAK)/信号转导和转录激活因子(Signal transducer and activator of transcription, STAT)信号通路是一条由细胞外至细胞核的信号转导极其快速的信号通路。目前在哺乳动物已鉴定出STAT家族的7个成员：STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b和STAT6。这其中以STAT3研究最为广泛。STAT3蛋白在细胞质中呈潜伏状态,被磷酸化后的STAT3即变为活化形式的STAT3 (p-STAT3),形成同源或异源二聚体,易位至细胞核与特定的启动子结合,诱导靶基因(如PTTG、VEGF、MMP2、Cyclin-Dl等)表达从而调控细胞增殖、分化、凋亡、血管形成等过程,如果STAT3被激活后持续活化可导致上述靶基因异常高表达,从而表现出致癌作用。目前,关于垂体腺瘤组织中STAT3表达和激活情况以及与下游靶基因PTTG的关系,国内外尚未见专题报道。目的通过免疫组化、Western blot. Real Time PCR检测垂体腺瘤组织中STAT3、 p-STAT3. PTTG蛋白和mRNA表达水平,分析这三种基因编码蛋白在垂体腺瘤发生发展中的作用以及STAT3、p-STAT3、PTTG与垂体腺瘤临床病理因素之间的关系,探讨STAT3调节PTTG的表达是否参与垂体腺瘤的致病过程。材料与方法垂体腺瘤标本来自2010年5月至2013年6月在北京协和医院神经外科接受手术治疗的80例垂体腺瘤患者。所有手术标本均经临床及病理诊断证实。肿瘤标本包括20例PRL腺瘤,20例ACTH腺瘤,20例GH腺瘤,20例NF腺瘤。其中,男性27例,女性53例,年龄17-58岁,平均40岁。所有病例均未进行包括化疗和放疗等术前治疗。根据Knosp标准,Ⅲ、Ⅳ级定义为侵袭性垂体腺瘤,Ⅰ、Ⅱ级定义为非侵袭性腺瘤,其中侵袭性腺瘤30例,非侵袭腺瘤共50例。结果1、免疫组化STAT3蛋白细胞核和细胞浆均有着色。STAT3蛋白在GH腺瘤的评分(6.15±2.90)显著高于PRL腺瘤(3.90±2.29) ACTH腺瘤(3.55±1.53)和NF腺瘤(1.85±1.73),差异具有统计学意义(p0.01)。PRL腺瘤和ACTH腺瘤中STAT3蛋白的评分差异无统计学意义(p=0.57)。NF腺瘤评分最低,与GH、PRL和ACTH腺瘤相比,差异具有统计学意义(p0.05)。上述结果被Western blot结果证实。2、免疫组化P-STAT3蛋白细胞核着色。p-STAT3蛋白在GH腺瘤的免疫组化评分最高(3.20±1.50),与其他三种类型肿瘤相比,差异具有统计学意义(p0.01)。PRL腺瘤(1.50±1.23)和ACTH腺瘤(1.15±1.39)评分次之,NF腺瘤评分最低(0.85±0.74),这三种类型之间比较,差异无统计学意义(p0.05)。上述结果被Western blot结果证实。3、免疫组化PTTG蛋白细胞浆着色。PTTG蛋白在GH腺瘤评分最高(2.05±0.99),与其他三种类型肿瘤相比,差异具有统计学意义(p0.05)。ACTH腺瘤(1.60±1.05)和PRL腺瘤(1.60±0.75)次之,NF腺瘤评分最低(1.40±1.05),以上三种类型肿瘤,差异无统计学意义(p0.05)。上述结果被Western blot结果证实。4、垂体腺瘤组织中STAT3、p-STAT3和PTTG蛋白表达与患者性别、肿瘤大小、肿瘤侵袭性均无关(p0.05)。5、STAT3蛋白和PTTG蛋白表达正相关(rk=0.437, p0.01), p-STAT3蛋白和PTTG蛋白表达正相关(rk=0.322,p0.01)。6. STAT3 mRNA和PTTG mRNA在PRL、ACTH、GH和NF腺瘤均有表达,其中以GH腺瘤表达较高。结论1、STAT3 mRNA和蛋白在垂体腺瘤组织中均有表达。2、垂体腺瘤组织中存在STAT3的持续激活。3、STAT3、p-STAT3、PTTG在不同类型垂体腺瘤表达水平不一,在GH腺瘤表达水平最高,NF腺瘤表达水平最低。4、垂体腺瘤中活化的STAT3可能通过促进下游靶基因PTTG的转录来发挥作用。
[Abstract]:Pituitary adenomas are common benign intracranial tumors, accounting for about 10%-25% of intracranial tumors. They originate from highly differentiated anterior pituitary cells secreting one or more hormones. According to the pathological types, pituitary adenomas can be divided into growth hormone (GH) adenomas, prolactin (PRL) adenomas, adrenocorticotrophin (ACH). Adenomas (ACTH) adenomas, nonfunctioning (NF) adenomas, and other types of tumors have different clinical manifestations, such as acromegaly, amenorrhea/galactorrhea, Cushing's syndrome, or just compression of the surrounding structures. Regardless of the pathological type, most pituitary adenomas grow slowly, but a few pituitaries. Adenomas are characterized by malignant biological behaviors, such as aggressive rapid growth, no response to conventional surgery, radiation, and drug therapy. Therefore, judging the biological behavior of the tumor is helpful to judge the prognosis and treatment of the tumor. Therefore, further study of the molecular biological mechanism of pituitary adenoma development, discovery of tumor markers and their clinical significance will be of great significance for the prevention, diagnosis, prognosis evaluation and treatment of pituitary adenoma. Janus protein tyrosine kinase (JAK) / signal transduction and transcription activation Signal transducer and activator of transcription (STAT) signaling pathway is an extremely fast signal transduction pathway from extracellular to nuclear. At present, seven members of STAT family have been identified in mammals: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. Among them, STAT3 is the most widely studied. STAT3 egg White is latent in the cytoplasm, and phosphorylated STAT3 becomes an activated form of STAT3 (p-STAT3), forming homologous or heterodimers, translocating to the nucleus and binding to specific promoters, inducing the expression of target genes (such as PTTG, VEGF, MMP2, Cyclin-Dl, etc.) to regulate cell proliferation, differentiation, apoptosis, angiogenesis and other processes, if STAT3 The expression and activation of STAT3 in pituitary adenoma tissues and the relationship between STAT3 and PTTG have not been reported at home and abroad.Objective To detect pituitary adenoma tissues by immunohistochemistry, Western blot and Real Time PCR. The expression levels of STAT3, p-STAT3. PTTG protein and mRNA in pituitary adenomas were analyzed. The relationship between STAT3, p-STAT3, PTTG and the clinicopathological factors of pituitary adenomas was analyzed. Whether the expression of STAT3 regulating PTTG was involved in the pathogenesis of pituitary adenomas was discussed. From May 2010 to June 2013, 80 patients with pituitary adenomas underwent surgical treatment in the Department of Neurosurgery, Peking Union Medical College Hospital. All surgical specimens were confirmed by clinical and pathological diagnosis. The tumor specimens included 20 PRL adenomas, 20 ACTH adenomas, 20 GH adenomas and 20 NF adenomas. Among them, 27 were males, 53 females, aged 17-58 years, with an average of 40 years. According to Knosp standard, grade III and IV were defined as invasive pituitary adenomas, grade I and II were defined as non-invasive adenomas, including 30 invasive adenomas and 50 non-invasive adenomas. Results 1. STAT3 protein was stained in the nucleus and cytoplasm of immunohistochemical staining. STAT3 protein was evaluated in GH adenomas. The score of STAT3 protein in PRL adenoma and ACTH adenoma was significantly higher than that in PRL adenoma (3.90 (+ 2.29)) ACTH adenoma (3.55 (+ 1.53)) and NF adenoma (1.85 (+ 1.73)). There was no significant difference in STAT3 protein between PRL adenoma and ACTH adenoma (p = 0.57). Results The Western blot results confirmed that. 2. P-STAT3 protein nuclear staining. P-STAT3 protein in GH adenoma had the highest immunohistochemical score (3.20 (+ 1.50). Compared with other three types of tumors, the difference was statistically significant (p0.01). PRL adenoma (1.50 (+ 1.23) and ACTH adenoma (1.15 (+ 1.39) were the second, and NF adenoma (0.85 (+ 0.7). There was no significant difference between the three types (p0.05). The above results were confirmed by Western blot. 3. The immunohistochemical PTTG protein cytoplasmic staining. PTTG protein in GH adenoma scored the highest (2.05.99), compared with other three types of tumors, the difference was statistically significant (p0.05). ACTH adenoma (1.60.05) and PRL adenoma (1.60.99). The expression of STAT3, p-STAT3 and PTTG protein in pituitary adenomas was not correlated with gender, tumor size and tumor invasion (p0.05). STAT3 protein and PTTG protein expression were positively correlated. (rk = 0.437, p0.01), p-STAT3 protein and PTG protein expression were positively correlated (rk = 0.322, p0.01). 6. STAT3 mRNA and PTG mRNA were expressed in PRL, ACTH, GH and NF adenomas, and GH adenomas were highly expressed. Conclusion 1. STAT3 mRNA and protein were expressed in pituitary adenomas. 2. There was a persistent activation of STAT3, STAT3, p-STAT3, and P-STAT3 in pituitary adenomas. The expression of PTTG was highest in GH adenomas and lowest in NF adenomas. Activated STAT3 in pituitary adenomas may play a role by promoting the transcription of PTTG.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R736.4
本文编号：2220754
[Abstract]:Pituitary adenomas are common benign intracranial tumors, accounting for about 10%-25% of intracranial tumors. They originate from highly differentiated anterior pituitary cells secreting one or more hormones. According to the pathological types, pituitary adenomas can be divided into growth hormone (GH) adenomas, prolactin (PRL) adenomas, adrenocorticotrophin (ACH). Adenomas (ACTH) adenomas, nonfunctioning (NF) adenomas, and other types of tumors have different clinical manifestations, such as acromegaly, amenorrhea/galactorrhea, Cushing's syndrome, or just compression of the surrounding structures. Regardless of the pathological type, most pituitary adenomas grow slowly, but a few pituitaries. Adenomas are characterized by malignant biological behaviors, such as aggressive rapid growth, no response to conventional surgery, radiation, and drug therapy. Therefore, judging the biological behavior of the tumor is helpful to judge the prognosis and treatment of the tumor. Therefore, further study of the molecular biological mechanism of pituitary adenoma development, discovery of tumor markers and their clinical significance will be of great significance for the prevention, diagnosis, prognosis evaluation and treatment of pituitary adenoma. Janus protein tyrosine kinase (JAK) / signal transduction and transcription activation Signal transducer and activator of transcription (STAT) signaling pathway is an extremely fast signal transduction pathway from extracellular to nuclear. At present, seven members of STAT family have been identified in mammals: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. Among them, STAT3 is the most widely studied. STAT3 egg White is latent in the cytoplasm, and phosphorylated STAT3 becomes an activated form of STAT3 (p-STAT3), forming homologous or heterodimers, translocating to the nucleus and binding to specific promoters, inducing the expression of target genes (such as PTTG, VEGF, MMP2, Cyclin-Dl, etc.) to regulate cell proliferation, differentiation, apoptosis, angiogenesis and other processes, if STAT3 The expression and activation of STAT3 in pituitary adenoma tissues and the relationship between STAT3 and PTTG have not been reported at home and abroad.Objective To detect pituitary adenoma tissues by immunohistochemistry, Western blot and Real Time PCR. The expression levels of STAT3, p-STAT3. PTTG protein and mRNA in pituitary adenomas were analyzed. The relationship between STAT3, p-STAT3, PTTG and the clinicopathological factors of pituitary adenomas was analyzed. Whether the expression of STAT3 regulating PTTG was involved in the pathogenesis of pituitary adenomas was discussed. From May 2010 to June 2013, 80 patients with pituitary adenomas underwent surgical treatment in the Department of Neurosurgery, Peking Union Medical College Hospital. All surgical specimens were confirmed by clinical and pathological diagnosis. The tumor specimens included 20 PRL adenomas, 20 ACTH adenomas, 20 GH adenomas and 20 NF adenomas. Among them, 27 were males, 53 females, aged 17-58 years, with an average of 40 years. According to Knosp standard, grade III and IV were defined as invasive pituitary adenomas, grade I and II were defined as non-invasive adenomas, including 30 invasive adenomas and 50 non-invasive adenomas. Results 1. STAT3 protein was stained in the nucleus and cytoplasm of immunohistochemical staining. STAT3 protein was evaluated in GH adenomas. The score of STAT3 protein in PRL adenoma and ACTH adenoma was significantly higher than that in PRL adenoma (3.90 (+ 2.29)) ACTH adenoma (3.55 (+ 1.53)) and NF adenoma (1.85 (+ 1.73)). There was no significant difference in STAT3 protein between PRL adenoma and ACTH adenoma (p = 0.57). Results The Western blot results confirmed that. 2. P-STAT3 protein nuclear staining. P-STAT3 protein in GH adenoma had the highest immunohistochemical score (3.20 (+ 1.50). Compared with other three types of tumors, the difference was statistically significant (p0.01). PRL adenoma (1.50 (+ 1.23) and ACTH adenoma (1.15 (+ 1.39) were the second, and NF adenoma (0.85 (+ 0.7). There was no significant difference between the three types (p0.05). The above results were confirmed by Western blot. 3. The immunohistochemical PTTG protein cytoplasmic staining. PTTG protein in GH adenoma scored the highest (2.05.99), compared with other three types of tumors, the difference was statistically significant (p0.05). ACTH adenoma (1.60.05) and PRL adenoma (1.60.99). The expression of STAT3, p-STAT3 and PTTG protein in pituitary adenomas was not correlated with gender, tumor size and tumor invasion (p0.05). STAT3 protein and PTTG protein expression were positively correlated. (rk = 0.437, p0.01), p-STAT3 protein and PTG protein expression were positively correlated (rk = 0.322, p0.01). 6. STAT3 mRNA and PTG mRNA were expressed in PRL, ACTH, GH and NF adenomas, and GH adenomas were highly expressed. Conclusion 1. STAT3 mRNA and protein were expressed in pituitary adenomas. 2. There was a persistent activation of STAT3, STAT3, p-STAT3, and P-STAT3 in pituitary adenomas. The expression of PTTG was highest in GH adenomas and lowest in NF adenomas. Activated STAT3 in pituitary adenomas may play a role by promoting the transcription of PTTG.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R736.4
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相关期刊论文 前1条
1 龚龙波;罗学来;刘双又;陶德定;龚建平;胡俊波;;GRIM-19及其靶基因产物STAT3与结直肠癌恶性程度的关系[J];癌症;2007年07期
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