非小细胞肺癌中S100A2、S100A4及S100P表达及意义

目的研究钙结合蛋白S100家族中S100A2、S100A4及S100P基因在非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达,阐明其与肺癌发生及转移的关系。方法以12例正常肺组织为对照,采用半定量RT-PCR技术检测17例腺癌和12例鳞癌及其癌旁组织中S100A2、S100A4及S100P mRNA的表达水平。结果(1)S100A2、S100A4及S100P mRNA在NSCLC中的表达量均高于癌旁和正常组织。(2)肺腺癌中三者mRNA表达量均高于癌旁和正常组织;肺鳞癌中S100A4和S100P mRNA的表达量高于正常组织。(3)根据不同的临床分期,S100A2、S100A4 mRNA在Ⅱ期与Ⅲ期中的表达量均高于Ⅰ期;S100P mRNA在Ⅲ期中的表达量高于Ⅰ期。(4)根据有无淋巴结转移,三者mRNA在有淋巴结转移癌组织中的表达量均高于无淋巴结转移的癌组织。(5)根据有无静脉癌栓,S100A4 mRNA在有静脉癌栓的癌组织中的表达量高于无静脉癌栓的癌组织。结论S100A4、S100A6、S100P在NSCLC中表达增加,尤其是在有淋巴结转移及TMN分期越高的癌组织中表...     

Non-expression of von Hippel-Lindau phenotype in an obligate gene carrier

Von Hippel-Lindau disease is generally considered to be a condition with very high penetrance, and individuals who live beyond the age of 60 years without showing any features of the disease, despite undoubtedly carrying the gene defect, have not previously been clearly described. The case is presented of a 65-year-old woman, who had four siblings affected with von Hippel-Lindau disease and had six children, three of whom died young with complications of von Hippel-Lindau disease. Although she is an obligate gene carrier, she has not developed any significant manifestations of the disease despite careful screening for the neurological, retinal and renal complications.     

Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma.

Adenoid cystic carcinoma is an indolent salivary gland malignancy that is associated with a poor long-term prognosis. The distinction of adenoid cystic carcinoma from other head and neck neoplasms can occasionally be problematic, particularly in small biopsies. Recent studies suggest that KIT (CD117) might be useful as an ancillary marker for adenoid cystic carcinoma; however, the expression of KIT in other benign and malignant head and neck neoplasms, including those that might mimic adenoid cystic carcinoma, has not been well studied. Here we use two different antibodies against KIT to evaluate its expression in a series of 66 adenoid cystic carcinomas compared with its expression in 98 other neoplasms of the head and neck. Overall, 94% (n = 62) of adenoid cystic carcinomas from various anatomic sites and of various histologic subtypes were positive for at least one of the KIT antibodies, and 77% (n = 50) of adenoid cystic carcinoma cases were positive for both antibodies. This contrasted with only 8% (n = 8) of other head and neck neoplasms that were positive for both KIT antibodies (P <.001). It was of note that certain neoplasms, including pleomorphic adenoma, basal cell adenoma, polymorphous low-grade adenocarcinoma, and basal cell carcinoma, that can show histologic overlap with adenoid cystic carcinoma had significantly less KIT immunoreactivity than did adenoid cystic carcinoma (P <.001). In contrast, KIT expression did not reliably distinguish adenoid cystic carcinoma from basal cell adenocarcinoma and basaloid squamous carcinoma (P >.05). The overall sensitivity of the two KIT antibodies for adenoid cystic carcinoma was 82-89%, and the specificity was 87-88%. The findings in this study support the potential use of KIT immunoexpression for distinguishing adenoid cystic carcinoma from many other benign and malignant head and neck neoplasms.     

Expression of the angiopoietins and their receptor Tie2 in human renal clear cell carcinomas; regulation by the von Hippel-Lindau gene and hypoxia

Angiogenesis is essential for tumour growth and metastasis, and is co-ordinated by several classes of angiogenic factors. To determine the significance and regulation of the angiopoietin (Ang) pathway in highly vascular human renal cell carcinomas (RCCs), this study has investigated the expression of the Ang-1, Ang-2, Ang-4, and Tie2 genes in a series of normal (n = 26) and neoplastic (n = 45; clear cell n = 35, papillary n = 10) human kidney tissues, examined the pattern of Ang-2 and Tie2 protein expression, and correlated expression with clinicopathological variables. The effect of the von Hippel-Lindau (VHL) gene and hypoxia in the renal cell lines RCC786-0 and RCC4 has also been investigated. Ang-1, Ang-2 and Tie2, but not Ang-4 mRNA, were detected in normal and tumour samples. A significant increase in Ang-2 (p < 0.001) and a decrease in Tie2 receptor mRNA (p = 0.001) were observed, but no significant difference was observed in Ang-1 mRNA abundance between normal kidney and RCC (p = 0.37). Immunohistochemistry for Ang-2 showed strong expression in vascular endothelium and weak expression in tumour cells, whereas Tie2 was expressed exclusively on endothelium. Tie2 gene expression was positively correlated with Ang-2 expression in cancers (p = 0.001) and showed a borderline significant association with Ang-1 (p = 0.06), but there was no significant relationship between Ang-1 and Ang-2 (p = 0.69). No significant relationships were observed in clear cell carcinomas between Ang-1, Ang-2 and Tie2 mRNA abundance and patient sex, patient age, or tumour size (p > 0.05). However, there was significantly greater Ang-1 (p = 0.02), Ang-2 (p = 0.03), and Tie2 (p = 0.04) mRNA abundance in clear cell than in chromophil RCCs. Ang-2 gene expression was down-regulated by hypoxia in VHL wild-type RCC786-0 and RCC4 transfectants (p = 0.0002 and p = 0.04, respectively), mirroring the low expression in human tumour cells. These data suggest that it is endothelial induction of Ang-2 in tumours that regulates vessel stability and supports targeting Tie2 as an effective novel anti-angiogenic therapy in clear cell RCCs.     

良、恶性前列腺组织中S100P与Ki-67的表达

目的观察人良、恶性前列腺组织中S100P与Ki-67的表达及二者的相关性。方法应用免疫组化SP法检测15例正常前列腺组织、30例前列腺增生(prostatic hyperplasia,BPH)及30例前列腺癌(prostate cancer,PCa)组织中S100P与Ki-67的表达,并分析二者在PCa组织中的表达有无相关性。结果 (1)S100P蛋白在正常前列腺组织及BPH组织中的阳性率(93.33%、90.00%)明显高于前列腺癌组(20.00%)(χ2=38.953,P<0.01);S100P蛋白在高、中、低分化PCa组织中阳性率差异无统计学意义(P>0.05)。(2)Ki-67在PCa组织中阳性率(63.33%)明显高于BPH(13.33%)及正常对照组(6.67%)(χ2=22.763,P<0.01);低分化PCa组Ki-67阳性率比高、中分化组明显增高(P<0.05)。(3)PCa组织中S100P和Ki-67二者表达呈负相关关系,但无统计学意义(r=-0.077,P=0.689)。结论前列腺发生癌变后S100P与Ki-67表达分别会发生下调与升高,可能预示肿瘤更具增殖能力和侵袭性,联合检测二者有助于判断PCa的发展趋势及预后评估。     

Expression of P-glycoprotein (multidrug-resistance gene product) in haematological tumors

The fact that cancer cell acquires multidrug resistance to carcinostatics at cancer treatment is a very important subject clinically. The mode of multidrug-resistance is complicated, but the gene associated with multidrug resistance (MDR 1) has been isolated. It has become evident that MDR 1 gene carries membrane glycoprotein (P-glycoprotein) which occurs in the cell acquired drug-resistance. Assessment has been made this time regarding the occurrence of P-glycoprotein in the tumorous cells and tissues by the use of monoclonal antibody (C 219) to P-glycoprotein. Occurrence of P-glycoprotein in malignant lymphoma exhibited positivity in 9 cases out of 36 immunohistologically. 170 KD P-glycoprotein was detected in 4 cases out of 10 at Western blotting analysis of the protein isolated from the nuclear cell in the peripheral blood in the patients with leukemia. Further, P-glycoprotein positive cases were all progressive cases clinically and showed resistance to treatment. From these results, it has been clarified that occurrence of P-glycoprotein in haematological tumors is related to multidrug resistance.     

Allelic deletion and mutation of the von Hippel-Lindau (VHL) tumor suppressor gene in pancreatic microcystic adenomas.

An association between pancreatic microcystic (serous) adenomas (MCAs) and von Hippel-Lindau (VHL) disease has been suggested. However, genetic alterations of the VHL gene in MCAs of the pancreas have never been reported. In this study, we performed genetic analysis of 12 pancreatic MCAs. In 2 cases, VHL disease was documented clinically, and 10 cases were sporadic. For LOH analysis, tumor and normal pancreatic cells were procured from formalin-fixed, paraffin-embedded material using tissue microdissection. After DNA extraction, the samples were amplified by polymerase chain reaction using the polymorphic markers D3S2452, D3S1110, D3S192, and D3S656. In addition, the sporadic tumors were analyzed for VHL gene mutations using probes 3b/10b and K55/K56. Both MCAs associated with VHL disease showed LOH with at least one of the microsatellite markers tested. Among the 10 sporadic cases, 7 tumors showed LOH at the VHL gene locus. A somatic VHL gene mutation on exon 2 was documented in one sporadic case. The study provides the first direct genetic evidence for the role of the VHL gene in MCA tumorigenesis. Furthermore, VHL gene alterations may be detected in both VHL-associated and sporadic pancreatic MCAs.     

Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population

Mutational inactivation of the VHL gene is the cause of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome predisposing to haemangioblastomas, pheochromocytomas and clear-cell renal carcinomas. The gene product (pVHL) functions as an adapter in cellular processes including cell growth and apoptosis. VHL mutation analysis was carried out in 426 unrelated subjects with phenotypes ranging from VHL syndrome, to isolated VHL-related tumours that could represent the first manifestation of the disease. A total of 111 individuals were found to carry alterations, with large deletions representing 40% of the variants. Eighteen of the 95 detected variants were novel, seemingly disease-causing mutations; their pathogenic role has been evaluated in silico for effects on protein folding and interactions. Putative regions of interaction between pVHL and proteins involved in common pathways have been identified, assessing possible implications for the presence of mutations in these regions. All new variants predicted to truncate or cause complete pVHL loss of structure were associated with phenotypes consistent with VHL type 1. Seven of the new amino acid substitutions are disease-causing mutations, one is a neutral variant, whereas the results for two remain ambiguous. Our combined molecular and in silico approach for the evaluation of putative disease-causing mutations contributes to the interpretation of the potential pathogenicity of these novel variants.