Kadian Lokesh Kumari, Gulshan Gulshan, Ahuja Parul, Singhal Geetanjali, Sharma Shivkant, Nanda Smiti, Yadav Ritu
Department of Genetics, Maharishi Dayanand University Rohtak, Haryana, India.
Department of Biosciences and Bioengineering, IIT Bombay Mumbai, Maharashtra, India.
Am J Transl Res. 2020 Jun 15;12(6):2814-2826. eCollection 2020.
Cervical cancer is the fourth most common type of cancer in women worldwide, and associated mortality is highest in developing countries like India. Limited studies are available on the role of NOTCH signaling pathway and promoter methylation in cervical cancer. In the current study, we investigated the promoter methylation status of NOTCH receptor genes (mainly , and ) and its correlation with gene expression, clinicopathological factors, and prognosis of cervical cancer. A total cohort of 110 cervical cancer patients of North Indian origin was enrolled in the study. From 28 of these patients, biopsies from adjacent non-cancerous tissue were available to serve as healthy controls. Promoter methylation status and mRNA expression level of , and were determined by methylation-specific PCR (MSP) and real-time quantitative (RT-qPCR), respectively. and promoters were methylated in 92% (P<0.0001), and 61% (P<0.001) of the cervical cancer biopsies. We did not observe a statistically significant change in the promoter methylation level of . Further, , and were down-regulated in cervical cancer biopsies, but the differential expression of only was found statistically significant. The promoter methylation levels of all three genes also showed a statistically significant association with clinicopathological factors and HPV infection (Type 16 and 18) but we did not observe a statistically significant relationship between their methylation status and gene expression. Overall our results provide evidence of the altered methylation and expression status of and receptor genes in cervical cancer. This study of NOTCH gene promoter methylation may provide a new perspective for early screening and diagnosis of cervical cancer.
宫颈癌是全球女性中第四大常见癌症类型,在印度等发展中国家,其相关死亡率最高。关于NOTCH信号通路和启动子甲基化在宫颈癌中的作用,现有研究有限。在本研究中,我们调查了NOTCH受体基因(主要是 、 和 )的启动子甲基化状态及其与基因表达、临床病理因素和宫颈癌预后的相关性。本研究共纳入了110名北印度裔宫颈癌患者。其中28名患者可获取相邻非癌组织的活检样本作为健康对照。分别通过甲基化特异性PCR(MSP)和实时定量(RT-qPCR)测定 、 和 的启动子甲基化状态和mRNA表达水平。在92%(P<0.0001)和61%(P<0.001)的宫颈癌活检样本中, 和 的启动子发生了甲基化。我们未观察到 的启动子甲基化水平有统计学显著变化。此外,在宫颈癌活检样本中 、 和 表达下调,但仅 的差异表达具有统计学显著性。所有三个基因的启动子甲基化水平也与临床病理因素和HPV感染(16型和18型)存在统计学显著关联,但我们未观察到它们的甲基化状态与基因表达之间存在统计学显著关系。总体而言,我们的结果提供了宫颈癌中 和 受体基因甲基化和表达状态改变的证据。这项关于NOTCH基因启动子甲基化的研究可能为宫颈癌的早期筛查和诊断提供新的视角。