Srivastava Shikha, Shahi Uday Pratap, Divya Arti, Gupta Sadhana, Singh Indu, Roy Jagat Kumar
Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, India.
Department of Radiotherapy and Radiation Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India .
Int J Mol Cell Med. 2020 Fall;9(4):273-288. doi: 10.22088/IJMCM.BUMS.9.4.273. Epub 2021 Jan 27.
Integration of human papilloma virus (HPV) in human genome is a random event, and fragile sites are one of the most susceptible sites for viral integrations. (WW-domain containing oxidoreductase) gene harbours the second most common fragile site, FRA16D, and can be an important candidate for HPV integration and cervical carcinogenesis. Our aim was to evaluate the potential role of in cervical carcinogenesis. Presence of HPV and its genotype was detected by PCR in normal cervix tissues and human cervical carcinoma. The expression of transcript and its protein was examined by RT-PCR, RNA hybridization, and immunoblotting. Southern blotting and sequencing were used to determine the alternative transcripts of . Statistical analysis were performed by Mann Whitney U-test, Pearson correlation coefficient test at significance level of P value < 0.05. Prevalence of HPV was observed in cervicitis (40%), cervical intraepithelial neoplasia patients (50%), and invasive cervical carcinoma patients (89.6%). Clinicopathological findings suggested a correlation of reduced level of WWOX protein and progression of cervical carcinoma deciphering its role in tumorigenesis. Furthermore, we observed aberrant transcript having deleted exon 6-8 region in invasive cervical cancer tissues as well as normal cervix samples. More than 60% of cervical carcinoma samples showed reduced protein level with an increase in wild type transcript level suggesting the involvement of a negative regulator, pAck1 (activated Cdc42- associated kinase) which might ubiquitinate WWOX protein leading to its degradation. Also, nuclear retention of transcript in invasive cervical carcinoma tissues suggests its regulation at post-transcriptional level. Our findings suggest that acts as a tumor suppressor in cervical carcinoma and could act as a potential therapeutic target for the disease.
人乳头瘤病毒（HPV）整合到人类基因组中是一个随机事件，而脆性位点是病毒整合最易感的位点之一。含WW结构域的氧化还原酶（WW-domain containing oxidoreductase）基因含有第二常见的脆性位点FRA16D，可能是HPV整合和宫颈癌发生的重要候选基因。我们的目的是评估其在宫颈癌发生中的潜在作用。通过PCR检测正常宫颈组织和人宫颈癌组织中HPV的存在及其基因型。通过RT-PCR、RNA杂交和免疫印迹检测其转录本及其蛋白质的表达。采用Southern印迹和测序确定其可变转录本。采用Mann Whitney U检验、Pearson相关系数检验进行统计学分析，显著性水平为P值<0.05。在宫颈炎患者（40%）、宫颈上皮内瘤变患者（50%）和浸润性宫颈癌患者（89.6%）中观察到HPV的流行情况。临床病理结果表明，WWOX蛋白水平降低与宫颈癌进展相关，揭示了其在肿瘤发生中的作用。此外，我们在浸润性宫颈癌组织以及正常宫颈样本中观察到异常转录本缺失外显子6-8区域。超过60%的宫颈癌样本显示蛋白水平降低，而野生型转录本水平升高，提示存在一种负调节因子pAck1（活化的Cdc42相关激酶）参与其中，它可能使WWOX蛋白泛素化导致其降解。此外，浸润性宫颈癌组织中该转录本的核滞留表明其在转录后水平受到调控。我们的研究结果表明，其在宫颈癌中起肿瘤抑制作用，可能是该疾病的潜在治疗靶点。
