WWOX,the FRA16D gene: A target of and a contributor to genomic instability

WWOX is one of the largest human genes spanning over 1.11 Mbp in length at chr16q23.1‐q23.2 and containing FRA16D, the second most common chromosomal fragile site. FRA16D is a hot spot of genomic instability, prone to breakage and for causing germline and somatic copy number variations (CNVs). Consequentially WWOX is frequent target for deletions in cancer. Esophageal, stomach, colon, bladder, ovarian, and uterine cancers are those most commonly affected by WWOX deep focal deletions. WWOX deletions significantly correlate with various clinicopathological features in esophageal carcinoma. WWOX is also a common target for translocations in multiple myeloma. By mapping R‐loop (RNA:DNA hybrid) forming sequences (RFLS) we observe this to be a consistent feature aligning with germline and somatic CNV break points at the edges and core of FRA16D spanning from introns 5 to 8 of WWOX. Germline CNV polymorphisms affecting WWOX are extremely common in humans across different ethnic groups. Importantly, structural variants datasets allowed us to identify a specific hot spot for germline duplications and deletions within intron 5 of WWOX coinciding with the 5′ edge of the FRA16D core and various RFLS. Recently, multiple pathogenic CNVs spanning WWOX have been identified associated with neurological conditions such as autism spectrum disorder, infantile epileptic encephalopathies, and other developmental anomalies. Loss of WWOX function has recently been associated with DNA damage repair abnormalities, increased genomic instability, and resistance to chemoradiotherapy. The described observations place WWOX both as a target of and a contributor to genomic instability. Both of these aspects will be discussed in this review.     

抑癌基因WWOX在哈萨克族食管鳞癌中表达的研究

目的探讨哈萨克族食管鳞癌中抑癌基因WWOX表达及意义,为哈萨克族的食管癌的早期诊断提供依据。方法收集新疆哈萨克族食管鳞癌患者癌组织、癌旁组织和正常食管组织标本各20例,HE染色观察癌组织的细胞学分型;免疫组化检测各组标本中WWOX的表达;RT-PCR检测各组标本中WWOX mRNA的表达。结果 WWOX蛋白在哈萨克族食管正常组织(65%)、癌旁组织(45%)及食管癌组织中(20%)的表达依次降低,各组间比较差异有统计学意义(P<0.05);WWOX mRNA的表达量在食管正常组织、食管癌旁组织及食管癌组织中的表达也依次降低,组间比较差异有统计学意义(P<0.05)。结论抑癌基因WWOX的低表达可能与哈萨克族食管癌的发生有关,对其表达的检测可能会成为哈萨克族食管癌早期诊断手段之一。     

miR‐134 induces oncogenicity and metastasis in head and neck carcinoma through targeting WWOX gene

Head and neck squamous cell carcinoma (HNSCC) is a prevalent disease worldwide, and the survival of HNSCC has not improved significantly over the last few decades. MicroRNAs (miRNAs) have an important regulatory role during carcinogenesis. Our study investigated the pathogenic implications of miR‐134 in head and neck carcinogenesis. The clinicopathologic implications of miR‐134 in HNSCC were investigated using expression assays and the functional role of miR‐134 in HNSCC pathogenesis was determined using ectopic expression, knockdown and reporter assay experiments. Xenographic tumorigenesis and orthotopic nodal metastasis were assayed in mouse models. In situ hybridization and immunohistochemistry were used to detect the expression of miR‐134 and the WWOX gene in human HNSCC. The results indicated that miR‐134 was upregulated in HNSCC tissues relative to control mucosa. High expression of miR‐134 was associated with nodal metastasis and mortality of patients. Decreased plasma miR‐134 levels after tumor ablation indicated a better prognosis for patients. Multivariate analysis showed that high miR‐134 expression in HNSCC was an independent predictor of poor survival. Ectopic miR‐134 expression significantly enhanced in vitro oncogenic phenotypes and the orthotopic growth and metastasis of HNSCC cells. miR‐134 targeted WW domain‐containing oxidoreductase (WWOX) gene and cell invasion enhanced by miR‐134 expression was abrogated by ectopic WWOX expression in HNSCC cells. miR‐134 expression was reversely associated with the WWOX expression in HNSCC tissues. Evidences from our study substantiated that miR‐134 expression contributes to head and neck carcinogenesis by targeting the WWOX.     

抑癌基因WWOX和p53在结直肠癌中的表达及临床意义

目的:探讨WWOX和p53基因在结直肠癌组织中的表达情况、与临床病理参数的关系及两者表达的相关性.方法:采用免疫组织化学染色法(SP法)检测对照组正常结直肠组织25例、结直肠癌组织45例中WWOX和P53蛋白的表达情况,分析两者的表达与患者年龄、性别及癌组织的病理参数包括肿瘤大小、浸润深度、淋巴结转移的关系,以及两者表达的相关性.结果:WWOX蛋白在癌组织中阳性表达明显降低,与正常组织比较差异有统计学意义(P＜0.05),P53(突变型)蛋白在癌组织中较正常结直肠组织中阳性表达率高,差异有统计学意义(P＜0.05).无论WWOX,还是P53蛋白的阳性表达率,在不同癌组织学分化程度、浸润深度、淋巴结转移情况、生存期分类的患者结直肠癌组织差异均有统计学意义(P＜0.05或P＜0.01),而在不同性别、年龄、肿瘤大小分类患者差异无统计学意义(P＜0.05);WWOX与p53基因的表达呈负相关(r=-0.388,P=0.008).结论:WWOX和p53(野生型)同为抑癌基因,检测两者的表达对于结直肠癌的临床诊断及预后判断有重要意义.     

FHIT、WWOX蛋白在子宫内膜癌中的表达及临床意义

目的 探讨脆性位点抑癌基因FHIT和WWOX蛋白在子宫内膜癌的表达及临床意义.方法 对56例肿瘤标本应用免疫组织化学SP法检测FHIT和Ww0X蛋白在子宫内膜癌组织中的表达.结果 FHIT和WWOX两种基因蛋白表达与子宫内膜癌临床分期、组织学分级厦淋巴结转移密切相关(P<0.05).在同一标本中,二者表达有密切相关性和较好的一致性(P<0.05).结论 FHIT和WWOX蛋白的表达与卵巢上皮性癌的浸润和转移密切相关,检测其表达异常对判断肿瘤的分化、临床进展以及推测预后有一定的参考价值[1].