Dissertation > Excellent graduate degree dissertation topics show

Succinate Dehydrogenase B Mutations and EPAS1 Overexpression Predict Invasion and Metastasis of Pheochromocytomas or Paragangliomas

Author: DengJianHua
Tutor: LiHanZhong;JiZhiGang;MaoQuanZong
School: Beijing Union Medical College
Course: Department of Urology
Keywords: Pheochromocytoma / paraganglioma Succinate dehydrogenase B Hypoxia-inducible factor Insulin-like growth factor Tissue microarray
CLC: R736.6
Type: PhD thesis
Year: 2011
Downloads: 51
Quote: 0
Read: Download Dissertation

Abstract


Purpose: pheochromocytoma (PHEO) and paraganglioma (PGL) is a tumor of the adrenal medulla and ganglia of the abdomen, chest, head and neck sources. Function (secretion of catecholamines) and cases of non-functional gene mutations account for about 30%. In addition to the RET, VHL and outside NF-1 encoding succinate dehydrogenase complex subunit nuclear genes SDHB, SDHC, SDHD and SDHAF2 PHEO / PGL susceptibility genes. About 15% of PHEO / PGL patients by SDHB, SDHC and SDHD gene mutations cause hereditary pheochromocytoma / paraganglioma syndrome (HPPS) gene mutation causes related protein expression with pheochromocytoma nerve section of tumor invasion and metastasis mechanism is not clear. The purpose of this study was to explore the relationship of SDHB mutations and EPAS1 overexpression PHEO / PGL invasion and metastasis, and to identify the gene mutation EPAS1, IGF-1 and MIB-1 index as malignant lesions predict clinical significance. Materials and methods: 1. SDH, VHL and RET germline mutations in the gene analysis of 43 cases of patients with PHEO / PGL. And clinical characteristics, including gender, age, tumor site and frequently-occurring disease change line correlation analysis results. The SDHB Gene (1q36.1-1q35, outer exons 1-8), SDHC gene (1q21, outer exons 1-5), SDHD gene (11q23, exon sub 1 to 4), SDHAF2 gene (11q12.2 , exons 1-4), RET proto-oncogene (10q11.2, exons 10, 11, 13, 14 and 15 and 16), and the VHL gene (3p25.3, outside exons 1-3) directly for DNA sequence analysis, the simultaneous detection PHEO / PGL peripheral blood samples of succinate dehydrogenase in the degree of methylation of the B promoter region. 2 of 64 cases of PHEO / PGL paraffin sections of tissue specimens SDHB EPAS1, VEGF-1R, CgA and MIB-1 immunohistochemical staining. Identified as positive granular cytoplasmic staining, counting five high-power field, 200 cells / field, a total of 1,000 gt; 50% strongly positive (), 11% -50% as moderately positive (), weakly positive diffuse cytoplasmic light dye and the lack of a clear positive particles, negative comparison with known positive internal reference, no staining. 3 Previous studies have shown activation of the insulin-like growth factor I receptor (IGF-IR) can produce strong neuroprotective effects, we study IGF-Ⅰ rat pheochromocytoma PC-12 cell differentiation and proliferation ability of PC12 cells is placed in the recombinant human IGF-1 environment, to observe the regulation of IGF-1 stimulation of the proliferation and differentiation of PC12 cells and the release of catecholamines. Results: 1. Gene mutation in 17 cases (17.5%, 17/97). The most common is the RET proto-oncogene mutations (8.24%, 8/97), seven patients with SDHB gene mutation (7.2%, 7/97), two cases of VHL gene mutation (2.06%, 2/97). Or the clinical features of the mutation in two groups statistically significant difference. 2. EPAS1 negative staining in normal adrenal medulla, pheochromocytoma tumor and paraganglioma moderate positive expression in benign, highly expressed in malignant paraganglioma. 17 patients with known VHL, RET and SDHB mutations of the tumor 15 cases showed positive staining. The case of VHL disease pheochromocytoma stained weakly positive. Germline gene mutations in 46 tumor specimens, 13 cases were positive. A clinical features consistent with familial paraganglioma specimens, but no SDH gene mutations into the negative, immunohistochemistry was weak diffuse staining. In addition, correlation analysis, EPAS1 positive expression of CgA, MIB-1, VEGF-1R, and CD34 are closely related. Experimental results show that 3.IGF-1 affect the proliferation and differentiation of PC-12 cells: compared with the addition of norepinephrine (NE), recombinant human IGF-1 by activating different signaling pathways, synergistic increase in rat pheochromocytoma PC12 The efficiency of cell proliferation and growth, and associated with a given dose and duration. Conclusion: Our study shows that: (1) genetic susceptibility chromaffin tissue tumors in the higher frequency, about 7.2% of paraganglioma SDHB germline gene mutations and SDHB mutations prevalent in the retroperitoneal paraganglioma and malignant paraganglioma; (2) SDHB gene mutation causes overexpression of paraganglioma EPAS1, thus making the downstream elements of CD34, VEGF-1R, IGF and TGF activation may be malignant invasion and metastasis One of the mechanisms; (3) IGF PHEO / PGL tumor cell differentiation and proliferation of regulatory networks. However, the complex regulation involving many factors, as well as multi-step synthesis and / or degradation, still need further study.

Related Dissertations

  1. Serum Levels of Insulin Like Growth Factor-1 and Cardiovascular Remodeling in Patients with Hypertension,R544.1
  2. Effects of Osteogenic Growth Peptide and Insulin-like Growth Factor-I on Biological Function in Cultured Human Periodontal Ligament Cell,R781.4
  3. The Mechanism of Lethal Effect of High-dose Vitamin C on Renal Cancer Cells,R737.11
  4. Concomitant exotropia rectus IGF-Ⅰ, AnnexinA1 expression,R779.6
  5. Insulin Promotes Proliferative Vitality and Invasive Capability of Pancreatic Cancer Cells Via Hypoxia-inducible Factor 1α Pathway,R735.9
  6. Expression of COX-2 and Hif-1α, and Its Correlation with Microvascular Angiogenesis in Cervical Cancer,R737.33
  7. Research on the Mechanism of Renal Impairment Induced by Chronic Intermittent Hypoxia and Reoxygenation,R692
  8. The Roles and Mechanism of HIF-2α in Pathogenesis of Ischemic/Hypoxic Acute Kidney Injury,R692
  9. Serum Insulin-like Growth Factor-1 Determination for Han Healthy Adults in Urumqi,R446.11
  10. Study on Relationship among Expression of IGF-1 in the Peri-Hematomal Brain Region, as Well as Excess Syndrome of Stroke and Prostration Syndrome in Intracerebral Hemorrhage Patients,R255.2
  11. The Study on the Experssions of IGF-1 and IGF-2 in Bone Marrow Mononuclear Cells and Supernatant of Chronic Mountain Sickness,R594
  12. The Relationship between Epithelial-mesenchymal Transition, the Expression of IGF-1R and Efficacy of Gefitinib as the Second Line Treatment for Advanced Non-small Cell Lung Cancer,R734.2
  13. Expression Changes of Hypoxia-inducible Factor-1 α and Aquaporin-4 in Brains of Rats after Cardio-pulmonary Resuscitation and the Intervention Effects of β-aescine Sodium,R459.7
  14. The Expression and Role of Igf2 and Igf2r in Infantile Hemangiomas,R732.2
  15. Pituitary growth hormone adenoma patients were followed up its secondary diabetes clinical study preoperative treatment,R736.4
  16. Effect of THH on Expressions of HIF-1α in Rats with Collagen Ⅱ-induced Arthritis,R285.5
  17. Yiqihuoxue side of peptic ulcer mucosa HIF-1α, VEGF intervention effect,R285
  18. Effect of Calcitonin on Osteoblasts IGF-1 Gene Expression in Simulated Microgravity,R85
  19. Small molecule IGF-1R inhibitor OSI-906 Synthesis of,O621.3
  20. The Effect of HIF-1α/SDF-1 Axis on Hypoxia-induced Progenitor Cell Migration and Adhesion,R363
  21. Expression of LIMK1 and uPAR in Human Colorectal Cancer by Tissue Microarray Analysis and Its Clinicopathological Significance,R735.34

CLC: > Medicine, health > Oncology > Internal endocrine tumors > Adrenal tumors
© 2012 www.DissertationTopic.Net  Mobile