垂体腺瘤分子生物学特征和手术治疗的研究
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摘要
目的 研究nucleostemin、ASPP2基因mRNA和Ki-67抗原在垂体腺瘤中的表达情况,分析其与垂体腺瘤侵袭性、肿瘤大小、病理类型、卒中及性别等临床资料的关系,进一步分析nucleostemin、ASPP2基因在垂体腺瘤细胞增值和垂体肿瘤发生和发展中的作用。材料与方法收集2004年1月～2005年8月间我院神经外科手术切除垂体腺瘤标本71例。采用半定量RT-PCR方法检测垂体腺瘤标本中nucleostemin和ASPP2基因mRNA的表达情况,采用免疫组化方法检测垂体腺瘤石蜡切片中Ki-67抗原的表达情况。同时收集相关的临床资料。结果(1)本组71例垂体腺瘤手术标本均有nucleostemin基因mRNA表达,其中nucleostemin在PRL腺瘤中表达水平最高,在无功能腺瘤中表达最低,但不同病理类型之间差异无统计学意义(P>0.05)。(2)71例垂体腺瘤手术标本均有ASPP2基因mRNA表达,其中在PRL腺瘤中表达水平最低,在GH腺瘤中表达最高,但不同病理类型之间差异无显著性(p>0.05)。(3)Ki-67LI在功能性垂体腺瘤和无功能性垂体腺瘤之间差异有显著性(P<0.05)。在PRL腺瘤中表达最高,在无功能腺瘤中最低,泌乳素腺瘤和无功能腺瘤的Ki-67LI差异有高度显著性(P<0.01),泌乳素腺瘤和促性腺细胞腺瘤之间差异有显著性(P<0.05),无功能腺瘤和生长激素腺瘤、多激素腺瘤的Ki-67LI之间也存在显著性差异(P<0.05)。(4)在不同病理类型的垂体腺瘤中,患者的年龄之间存在差异(P<0.05),促性腺细胞腺瘤患者的平均年龄最高,ACTH腺瘤患者的平均年龄最低。促性腺细胞腺瘤患者的平均年龄和ACTH腺瘤患者的平均年龄之间存在高度显著性差异(p<0.01),促性腺细胞腺瘤患者的平均年龄和生长激素腺瘤患者的平均年龄之间存在显著性差异(P<0.05)。(5)nucleostemin、ASPP2mRNA及Ki-67LI在卒中垂体腺瘤和非卒中垂体腺瘤中的表达差异无显著性(P>0.05)。(6)侵袭性垂体腺瘤中的患者年龄、肿瘤平均长径、nucleostemin和ASPP2mRNA表达以及Ki-67LI均高于非侵袭垂体腺瘤。非侵袭垂体腺瘤和侵
Objective Study the expression of nucleostemin, ASPP2 gene mRNA and Ki-67 antigen in pituitary adenomas, analyze the relationship between the expression and clinical data, such as invasion, tumor diameter, pathology type, and so on. Assay the function of nucleostemin and ASPP2 gene on cell proliferation, tumorigenesis and developing in pituitary adenoma further. Methods 71 samples of pituitary adenomas were collected. Semi-quantitative reverse transcriptase-polymerase chain (RT-PCR) was used to detect expression of nucleostemin, ASPP2 gene mRNA in samples. Immunochemistry Technique was applied to examine Ki-67 expression in the paraffin section of samples. At the same time, coherent clinical data were collected. Results (1) Nucleostemin gene mRNA were detectable in all samples of pituitary adenomas. Nucleostemin expression was the highest in PRL adenoma, and it's the lowest in nonfunctional adenoma, but there was no statistical significance among different pathological type (P>0.05). (2) ASPP2 gene mRNA were detectable in all samples of pituitary adenomas. ASPP2 expression was the lowest in PRL adenoma, and it's the highest in GH adenoma, but there was no statistical significance among different pathological type (P>0.05). (3) Ki-67 LI was the highest in PRL adenoma, the lowest in nonfunctional adenoma, when contrast with each other, its of great statistical significance (P<0.01). Difference between PRL adenoma and GH adenoma was of statistical significance(P<0.05). Difference of Ki-67LI in nonfunctional adenoma, GH adenoma and multi-hormone adenoma was of statistical significance(P<0.05). (4) The patients' age among different pathological types of adenoma is different(P<0.05). Average age of gonadotroph adenoma patients was the largest, ACTH adenoma patients' was the lowest. When contrast with each other, there existed great statistical significance (P<0.01). Patients average age of gonadotroph adenoma and GH adenoma was also different (P<0.05). (5) Nucleostemin, ASPP2 mRNA and Ki-67LI expression difference between apoplexia and non-apoplexia pituitary adenoma were not significant (P>0.05). (6) Patients' age,
tumor average diameter, nucleostemin mRNA, ASPP2 mRNA and Ki-67 expression were higher in invasive pituitary adenoma than that in noninvasive pituitary adenoma. Differences of tumor average diameter, nucleostemin and ASPP2 mRNA expression between them were extremely significant(P<0.01). And that of age and Ki-67 LI were significant. When compared with course and sex, they had no significant difference(P>0.05). Invasion was no significant difference between functioning and non-functioning pituitary adenomas(P>0.05). (7) There was 5 cases recur in the 64 follow-up patients (7.8%). Tumor average diameter, course, nucleostemin gene expression and Ki-67 LI were higher in recurrent group than that in non-recurrent group. Statistical results showed that difference of Ki-67 LI between them was significant(P<0.05), but other factors were of no statistical significance(P>0.05). (8) There was positive correlation between nucleostemin gene and KJ-67LI level(P<0.05). Correlation between ASPP2 and Ki-67LI was negative(P<0.05). A negative correlation was demonstrated between nucleostemin and ASPP2 expression(P<0.01). (9) Age and mean tumor diameter were significantly higher in men than in women (PO.001). Conclusions (1) Nucleostemin and ASPP2 gene might express in human pituitary adenoma tissues. (2) the expression differences of nucleostemin ASPP2 and Ki-67 in different pathological types of pituitary adenomas, represented differences in molecular biological character, relating with invasion. (3) In different pathological types of pituitary adenomas, the age existed difference, which shows that different age might have predilection in pathological type. (4) In pituitary adenoma, nucleostemin expression had positive correlation to tumor proliferation, thus ASPP2mRNA expression had negative correlation to tumor proliferation. (5) With higher nucleostemin and Ki-67, lower ASPP2, elder age, larger maximum diameter, the tumor had higher probability ratio to invasive. Tumor probability ratio to invasive had no difference in patients of different sex. (6) Ki-67LI might be a valid clinical detection marker to decision pituitary adenoma relapsing. (7) Among raising up of nucleostemin gene expression, depressing of ASPP2 gene expression and high Ki-67, there existed associativity in pituitary adenoma. (8) in patients of different sex, the age of morbility was difference.
Objective Study the expression of nucleostemin, ASPP2 gene mRNA and Ki-67 antigen in pituitary adenomas, analyze the relationship between the expression and clinical data, such as invasion, tumor diameter, pathology type, and so on. Assay the function of nucleostemin and ASPP2 gene on cell proliferation, tumorigenesis and developing in pituitary adenoma further. Methods 71 samples of pituitary adenomas were collected. Semi-quantitative reverse transcriptase-polymerase chain (RT-PCR) was used to detect expression of nucleostemin, ASPP2 gene mRNA in samples. Immunochemistry Technique was applied to examine Ki-67 expression in the paraffin section of samples. At the same time, coherent clinical data were collected. Results (1) Nucleostemin gene mRNA were detectable in all samples of pituitary adenomas. Nucleostemin expression was the highest in PRL adenoma, and it's the lowest in nonfunctional adenoma, but there was no statistical significance among different pathological type (P>0.05). (2) ASPP2 gene mRNA were detectable in all samples of pituitary adenomas. ASPP2 expression was the lowest in PRL adenoma, and it's the highest in GH adenoma, but there was no statistical significance among different pathological type (P>0.05). (3) Ki-67 LI was the highest in PRL adenoma, the lowest in nonfunctional adenoma, when contrast with each other, its of great statistical significance (P<0.01). Difference between PRL adenoma and GH adenoma was of statistical significance(P<0.05). Difference of Ki-67LI in nonfunctional adenoma, GH adenoma and multi-hormone adenoma was of statistical significance(P<0.05). (4) The patients' age among different pathological types of adenoma is different(P<0.05). Average age of gonadotroph adenoma patients was the largest, ACTH adenoma patients' was the lowest. When contrast with each other, there existed great statistical significance (P<0.01). Patients average age of gonadotroph adenoma and GH adenoma was also different (P<0.05). (5) Nucleostemin, ASPP2 mRNA and Ki-67LI expression difference between apoplexia and non-apoplexia pituitary adenoma were not significant (P>0.05). (6) Patients' age,
tumor average diameter, nucleostemin mRNA, ASPP2 mRNA and Ki-67 expression were higher in invasive pituitary adenoma than that in noninvasive pituitary adenoma. Differences of tumor average diameter, nucleostemin and ASPP2 mRNA expression between them were extremely significant(P<0.01). And that of age and Ki-67 LI were significant. When compared with course and sex, they had no significant difference(P>0.05). Invasion was no significant difference between functioning and non-functioning pituitary adenomas(P>0.05). (7) There was 5 cases recur in the 64 follow-up patients (7.8%). Tumor average diameter, course, nucleostemin gene expression and Ki-67 LI were higher in recurrent group than that in non-recurrent group. Statistical results showed that difference of Ki-67 LI between them was significant(P<0.05), but other factors were of no statistical significance(P>0.05). (8) There was positive correlation between nucleostemin gene and KJ-67LI level(P<0.05). Correlation between ASPP2 and Ki-67LI was negative(P<0.05). A negative correlation was demonstrated between nucleostemin and ASPP2 expression(P<0.01). (9) Age and mean tumor diameter were significantly higher in men than in women (PO.001). Conclusions (1) Nucleostemin and ASPP2 gene might express in human pituitary adenoma tissues. (2) the expression differences of nucleostemin ASPP2 and Ki-67 in different pathological types of pituitary adenomas, represented differences in molecular biological character, relating with invasion. (3) In different pathological types of pituitary adenomas, the age existed difference, which shows that different age might have predilection in pathological type. (4) In pituitary adenoma, nucleostemin expression had positive correlation to tumor proliferation, thus ASPP2mRNA expression had negative correlation to tumor proliferation. (5) With higher nucleostemin and Ki-67, lower ASPP2, elder age, larger maximum diameter, the tumor had higher probability ratio to invasive. Tumor probability ratio to invasive had no difference in patients of different sex. (6) Ki-67LI might be a valid clinical detection marker to decision pituitary adenoma relapsing. (7) Among raising up of nucleostemin gene expression, depressing of ASPP2 gene expression and high Ki-67, there existed associativity in pituitary adenoma. (8) in patients of different sex, the age of morbility was difference.
引文
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2. Riddihough G, Pennisi E.The evolution of epigenetics.Science, 2001, 293(5532): 1063.
3. Samuels-Lev Y, O'Connor DJ, Bergamaschi D, et al. ASPP proteins specifically stimulate the apoptotic function of p53.Mol Ce11, 2001, 8(4): 781-794.
4. Wilson CB. A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg, 1984, 61: 814-833.
5. Oruckaptan HH, Senmevsim O, Ozcan OE, et al. Pituitary adenomas: results of 684 surgically treated patients and review of the literature. Surg Neurol, 2000, 53: 211-219.
6. Abosch A, Tyrrell JB, Lambom KR, et al. Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab, 1998, 83: 3411-3418.
7.王忠诚,主编.王忠诚神经外科学.武汉:湖北科学技术出版社,2005.649-650.
8. Parl FF, Cruz VE, Cobb CA, et al. Aleshire SL.Late recurrence of surgically removed prolactinomas. Cancer, 1986, 57(12): 2422-2426.
9. Pei L, Melmed S, Scheithauer B, et al. H-ras mutations in human pituitary carcinoma metastases. J Clin Endocrinol Metab, 1994, 78(4): 842-846.
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