Low levels of WWOX protein immunoexpression correlate with tumour grade and a less favourable outcome in patients with urinary bladder tumours

Aims:  To correlate the immunohistochemical detection of WWOX with histological measures and disease progression within the whole spectrum of urothelial bladder neoplasms.
Methods and results:  One hundred and one patients with primary bladder tumours were retrospectively analysed. Immunohistochemically, a polyclonal antibody was utilized and the level of WWOX protein expression was analysed by using a combined score system based on intensity of the reaction and percentage of immunoreactive tumour cells. WWOX protein expression was consistently expressed in non-neoplastic urothelium, whereas a progressive loss of immunoreactivity was observed as tumour grade and stage increased ( P  < 0.05). Principal component analysis showed that reduced WWOX immunoexpression was significantly associated with high histological grades ( P  = 0.001), advanced stage ( P  = 0.002), tumour size ( P  = 0.04) and cancer progression ( P  = 0.028). Invasive urothelial carcinomas of the bladder with squamous metaplasia presented the lowest levels of WWOX protein. Kaplan–Meier analyses demonstrated a significant correlation between loss of WWOX expression and a shorter progression-free survival ( P  = 0.042), whereas the prediction of overall survival achieved borderline significance ( P  = 0.053).
Conclusion:  Loss of WWOX immunoexpression strongly correlates with classical clinicopathological factors and appears to be a potential predictive marker of progressive disease.     

抑癌基因WWOX与恶性肿瘤的关系研究进展

目的：探讨WW结构域氧化还原酶基因（WWOX）与肿瘤的关系,为临床提供理论依据.方法：在PubMed和中国期刊全文数据库中查阅近年来国内外有关文献,并做进一步综合分析.结果：WWOX位于人类普通型染色体脆性位点FRA16D上,在多种恶性肿瘤中表达下调或缺失,与WWOX作用相关的蛋白均处于信号转导的关键点.结论：WWOX可以增强多种抑癌基因的功能,抑制原癌基因的表达,从而发挥抑制肿瘤作用.     

WWOX与c-jun在胃癌中表达及其临床意义

目的研究WWOX与c-jun在胃癌中表达及其临床意义。方法应用免疫组化SP法检测60例原发性胃癌及其癌旁组织中WWOX与c-jun蛋白的表达情况。结果胃癌组织中WWOX蛋白阳性表达率(28.3%)显著低于在癌旁组织中的表达率(81.7%)(P<0.01)。胃癌组织中c-jun蛋白阳性表达率(68.3%)显著高于其癌旁组织中的表达率(23.3%)(P<0.01)。WWOX蛋白的阳性表达与肿瘤的分化程度有关(P<0.05),与其他临床病理参数无关。c-jun蛋白阳性表达与胃癌浸润深度、淋巴结转移有关(P<0.05)。两者的表达存在相关性(χ2=4.96,P<0.01)。结论WWOX蛋白和c-jun蛋白在胃癌组织和癌旁组织的表达均有明显的差异,WWOX蛋白在胃癌中低表达,而c-jun蛋白在胃癌中高表达。     

牙龈鳞癌中WWOX基因的表达及其临床意义

目的：研究WWOX基因在牙龈鳞癌组织中的表达及意义。方法：应用免疫组化SP法检测70例牙龈鳞癌组织中WWOX基因的表达,并与临床病理指标结合进行分析。结果：牙龈鳞癌组织中ww0X基因的阳性率为27．14％。WWOX基因的表达与牙龈鳞癌的病理分级、淋巴结转移有相关性（P〈0．05）,与临床分期明显相关（P〈0．05）。WWOX基因在牙龈鳞癌中的表达呈负相关性。结论：WWOX基因参与牙龈鳞癌的发生发展过程,可作为评估牙龈鳞癌生物学行为的一项指标,用于识别高危转移和不良预后者及为判断其生物学特性提供可靠的指标。     

抑癌基因WWOX在消化道肿瘤中的研究进展

WWOX基因定位于染色体16q23.3～24.1,位于染色体普通脆性位点FDR16D,包含9个外显子,编码414个氨基酸,WWOX可能与p53、Bmi1、survivin、p73、Ap2α/γ、c-Jun、ErbB4、Runx2等相互作用而发挥凋亡作用。在多种消化道肿瘤中均发现WWOX基因杂合子缺失,WWOX mRNA表达低下或缺失,WWOX蛋白表达水平低。     

Expression of Fragile Histidine Triad (FHIT) and WW-Domain Oxidoreductase Gene (WWOX) in Nasopharyngeal Carcinoma

The aim of the present study was to analyze the expression of FHIT and WWOX in nasopharyngeal carcinoma(NPC) and correlations with clinical pathologic features. mRNA expression of the FHIT and WWOX was assessedby real-time fluorescent relatively quantitative PCR in 61 NPC tissues and 45 non-cancerous nasopharyngealtissues. As a result, mRNA expression levels of both FHIT and WWOX were significantly lower in NPC patientsthan in control samples (P=0.049 and 0.045, respectively). Moreover, the mRNA expression of both had an inverserelation with larger invasive range (P=0.035 and 0.048, respectively), poor histologic differentiation (P=0.012 and0.016) and advanced clinical stage (P=0.026 and 0.038). Consistency was found between expression of FHIT andWWOX in the same NPC tissues (r=0.681, P=0.00). In conclusion, synergy between FHIT and WWOX may existin the development of NPC so that the two factors may be considered as important genetic markers. Detectingthe expression of FHIT and WWOX should provide clinically significant information relevatn to tumor diagnosis,progression and treatment modalities for NPC.     

Association study of a functional copy number variation in the WWOX gene with risk of gliomas among Chinese people

Gliomas represents more than 80% of all malignant brain tumors. However, the etiology still remains largely unknown. Human WW domain‐containing oxidoreductase (WWOX), which is located at 16q23.1–16q23.2, the common fragile site 16D (FRA16D), an area with a high frequency of gene deletions or chromosomal alterations, has been identified as a tumor suppressor gene in multiple cancers. In current study, we analyzed the WWOX deletion (CNV‐67048) in a large, case–control study of 3,622 adult Chinese people (including 1,798 glioma cases and 1,824 healthy controls). All participants were genotyped using real‐time qualitative PCR (qPCR), and its biological effect was validated with mRNA expression assays. The deletion was significantly associated with glioma risk, with ORs (95% CIs) of 1.21 (1.05–1.41) associated with 1 copy deletion and 1.94 (1.37–2.75) associated with 2 copy deletion as compared with subjects with no deletion (p for trend = 8.05 × 10^?6). Additional adjustments and stratified analyses did not change the results materially. The mRNA levels of WWOX in glioma tissues were significantly lower than that of their border tissues (p = 0.007), especially in the loss genotyped subjects. Our data suggest that the loss genotypes of CNV‐67048 in WWOX gene predispose their carriers to gliomas, and WWOX gene deletion may be a new biomarker for predicting risk of gliomas.     

抑癌基因WWOX及其与肿瘤关系的研究进展

在普通型脆性位点FRA16D上的新基因WWOX已被认为是与多种肿瘤相关的抑癌基因,其DNA序列、mRNA、蛋白结构已基本清楚,其促凋亡的作用已经肯定,然而具体的作用机制存在着争议。为进一步探讨研究其作用机制,对充分认识肿瘤发生机制及肿瘤的早期外科诊治具有重大意义。