非小细胞肺癌中WWOX蛋白及ErbB2蛋白的联合检测

 目的 探讨WWOX(WW domain-containing oxidoreductase)基因在非小细胞肺癌组织中的表达及与ErbB2蛋白之间的关系。 方法 用免疫组化方法检测50例肺鳞癌,31例肺腺癌及20例癌旁正常组织中WWOX基因蛋白的表达,并分析其与各临床病理指标及ErbB2蛋白之间的相关性。 结果 WWOX基因在72.8%的非小细胞肺癌中失表达或表达减少,而在癌旁正常组织中有80.0%正常表达。WWOX基因的表达与组织类型、细胞分化程度密切相关（P<0.05）,在鳞癌和低分化癌中WWOX基因失表达或表达减少的发生率更高。肺癌中ErbB2的过度表达与肺癌的临床分期、淋巴结转移相关,WWOX蛋白阳性表达与ErbB2负相关(r=–0.239,Ｐ<0.05)。 结论 WWOX蛋白的低表达与ErbB2的过表达可以协同判断预后较差的非小细胞肺癌。     

胃癌组织中FHIT和WWOX的表达与临床病理特征的关系

目的探讨脆性位点抑癌基因组氨酸三联体（FHIT）和包含WW域的氧化还原酶（WWOX）的蛋白在胃癌组织中的表达及其与临床病理特征的关系。方法采用免疫组化PV-9000二步法检测70例胃癌组织、30例癌旁正常组织中FHIT和WWOX基因的蛋白表达情况。结果胃癌组织中FHIT和WWOX蛋白阳性表达率明显低于癌旁正常组织（P〈0.05）,与胃癌临床分期、组织学分级及淋巴结转移密切相关（P〈0.05）,与年龄、性别、肿瘤大小无关（P〉0.05）。FHIT和WWOX蛋白表达之间有相关性（P〈0.05）。结论 FHIT和WWOX基因可能参与了胃癌的发生发展,两者在胃癌的发生发展过程中可能存在协同作用。     

New syngeneic inflammatory‐related lung cancer metastatic model harboring double KRAS/WWOX alterations

New mouse models with specific drivers of genetic alterations are needed for preclinical studies. Herein, we created and characterized at the genetic level a new syngeneic model for lung cancer and metastasis in Balb‐c mice. Tumor cell lines were obtained from a silica‐mediated airway chronic inflammation that promotes tumorigenesis when combined with low doses of N‐nitrosodimethylamine, a tobacco smoke carcinogen. Orthotopic transplantation of these cells induced lung adenocarcinomas, and their intracardiac injection led to prominent colonization of various organs (bone, lung, liver and brain). Driver gene alterations included a mutation in the codon 12 of KRAS (G–A transition), accompanied by a homozygous deletion of the WW domain‐containing oxidoreductase (WWOX) gene. The mutant form of WWOX lacked exons 5–8 and displayed reduced protein expression level and activity. WWOX gene restoration decreased the in vitro and in vivo tumorigenicity, confirming the tumor suppressor function of this gene in this particular model. Interestingly, we found that cells displayed remarkable sphere formation ability with expression of specific lung cancer stem cell markers. Study of non‐small‐cell lung cancer patient cohorts demonstrated a deletion of WWOX in 30% of cases, with significant reduction in protein levels as compared to normal tissues. Overall, our new syngeneic mouse model provides a most valuable tool to study lung cancer metastasis in balb‐c mice background and highlights the importance of WWOX deletion in lung carcinogenesis.     

Microarray analysis reveals down-regulation of the tumour suppressor gene WWOX and up-regulation of the oncogene TYMS in intracranial sporadic meningiomas

BACKGROUND: In order to investigate pathways that may influence on tumour development in meningiomas, we performed high throughput microarray analysis of the RNA expression and DNA copy number of 22 WHO grade I and five WHO grade II meningiomas. Since meningiomas derive from arachnoid cap cells, we used samples from four patients operated for arachnoid cysts as control tissue. RESULTS: The expression of the tumour suppressor gene WW containing oxidoreductase (WWOX) was down-regulated, and the thymidylate synthase (TYMS) oncogene was up-regulated in all meningiomas as compared to arachnoid cysts. Unsupervised RNA cluster analysis showed that fibrous meningiomas gathered in two clusters, and thus were more homogeneous than the other meningiomas. The other histological subgroups could not be linked to any uniform gene expression signatures. Rearrangements were most abundant on chromosomes 1 and 22, but were identified on all except chromosome 16. The fibrous and mixed meningiomas generally had chromosomal deletions. Duplications were more frequent in the meningothelial meningiomas. WHO grade II meningiomas had increased chromosomal instability. CONCLUSION: Decreased expression of the WWOX tumour suppressor gene and increased expression of the TYMS oncogene may be of importance for the development of human intracranial meningiomas. We have identified several genes (BMPR1B, DMD, RAMP1) with expression signatures specific for fibrous meningiomas. CGH analysis revealed distinct chromosomal patterns in relation to the histological subtypes of the meningiomas.     

Evidences that the polymorphism Pro-282-Ala within the tumor suppressor gene WWOX is a new risk factor for differentiated thyroid carcinoma

We report a hypothesis-driven study aimed to detect genetic markers of susceptibility to differentiated thyroid carcinomas (DTC). A large number of candidate genes were first selected through literature search (genome-wide studies were also included). To restrict the analysis to single nucleotide polymorphisms (SNPs) with a high likelihood to be associated with increased risk, each SNP must comply with several a priori hypotheses. Only one SNP, the rs3764340 encoding for the aminoacidic substitution proline-to-alanine at codon 282 of the tumor suppressor gene WWOX, passed the selection. A case-control association study was carried out, involving a total of 1,741 cases and 1,042 controls. The logistic regression analysis revealed an increased risk of DTC for the carriers of the G-allele (crude odds ratio, OR = 1.53; 95% confidence interval, CI = 1.18-1.99; p = 1.38 × 10(-3) ). When we controlled for covariates, the adjusted OR was 1.48 with a 95% CI of 1.08-2.03 (p = 8.0 × 10(-3) ). The association was confirmed after stratification for histology (for papillary thyroid carcinoma the adjusted OR was 1.43; 95% CI 1.02-2.00; p = 0.037), incident cases and smokers, but was also at the limit of statistical significance in all the other categories considered. In silico analyses showed that when alanine substitutes proline, subtle changes of the proteic structure can be predicted. These findings together with other observations from literature on human cancers and the fact that the proline at codon 282 is extremely conserved in phylogenetically distant organisms (including Drosophila) suggest that the variant allele-282 could affect the biological function of WWOX, thereby predisposing individuals to thyroid cancer.     

Investigation of osteosarcoma genomics and its impact on targeted therapy:an international collaboration to conquer human osteosarcoma

Osteosarcoma is a genetical y unstable malignancy that most frequently occurs in children and young adults. The lack of progress in managing this devastating disease in the clinic has prompted internat...     

非小细胞肺癌中Bmi-1和WWOX蛋白的表达及其临床意义

目的探讨非小细胞肺癌中BMi-1与WWOX蛋白的表达及其临床意义。方法应用免疫组化和Western blot检测86例非小细胞肺癌中Bmi-1蛋白和WWOX蛋白的表达水平,分析BMi-1与WWOX蛋白与临床患者特征的关系,并对患者生存影响因素进行分析。结果 Bmi-1蛋白在非小细胞肺癌中的表达水平显著高于癌旁正常组织中表达水平(0.01),而WWOX蛋白在非小细胞肺癌中的表达水平(0.52±0.05)则显著低于癌旁正常组织中表达水平(0.01)。Bmi-1和WWOX蛋白表达水平均与淋巴结转移有关(0.05)。结论 Bmi-1的高表达和WWOX蛋白的低表达均与淋巴结转移有关。     

WWOX induces apoptosis and inhibits proliferation of human hepatoma cell line SMMC-7721

AIM: To investigate the effects of the WWOX gene on the human hepatic carcinoma cell line SMMC-7721.METHODS: Full-length WWOX cDNA was amplified from normal human liver tissues. Full-length cDNA was subcloned into pEGFP-N1, a eukaryotic expression vector. After introduction of the WWOX gene into cancer cells using liposomes, the WWOX protein level in the cells was detected through Western blotting. Cell growth rates were assessed by methyl thiazolyl tetrazolium (MTT) and colony formation assays. Cell cycle progression and cell apoptosis were measured by flow cytometry. The phosphorylated protein kinase B (AKT) and activated fragments of caspase-9 and caspase-3 were examined by Western blotting analysis.RESULTS: WWOX significantly inhibited cell proliferation, as evaluated by the MTT and colony formation assays. Cells transfected with WWOX showed significantly higher apoptosis ratios when compared with cells transfected with a mock plasmid, and overexpression of WWOX delayed cell cycle progression from G1 to S phase, as measured by flow cytometry. An increase in apoptosis was also indicated by a remarkable activation of caspase-9 and caspase-3 and a dephosphorylation of AKT (Thr308 and Ser473) measured with Western blotting analysis.CONCLUSION: Overexpression of WWOX induces apoptosis and inhibits proliferation of the human hepatic carcinoma cell line SMMC-7721.