Sowjanya A Pavani, Rao Meera, Vedantham Haripriya, Kalpana Basany, Poli Usha Rani, Marks Morgan A, Sujatha M
Institute of Genetics and Hospital for Genetic Diseases, Begumpet, Telangana State, India.
Sir Ronald Ross Institute of Tropical and Communicable Diseases, Nallakunta, Hyderabad, Telangana State, India.
Nitric Oxide. 2016 Jan 30;52:21-8. doi: 10.1016/j.niox.2015.09.005. Epub 2015 Oct 3.
Cervical cancer is caused by infection with high risk human papillomavirus (HR-HPV). Inducible nitric oxide synthase (iNOS), a soluble factor involved in chronic inflammation, may modulate cervical cancer risk among HPV infected women. The aim of the study was to measure and correlate plasma nitrite/nitrate levels with tissue specific expression of iNOS mRNA among women with different grades of cervical lesions and cervical cancer. Tissue biopsy and plasma specimens were collected from 120 women with cervical neoplasia or cancer (ASCUS, LSIL, HSIL and invasive cancer) and 35 women without cervical abnormalities. Inducible nitric oxide synthase (iNOS) mRNA from biopsy and plasma nitrite/nitrate levels of the same study subjects were measured. Single nucleotide polymorphism (SNP) analysis was performed on the promoter region and Ser608Leu (rs2297518) in exon 16 of the iNOS gene. Differences in iNOS gene expression and plasma nitrite/nitrate levels were compared across disease stage using linear and logistic regression analysis. Compared to normal controls, women diagnosed with HSIL or invasive cancer had a significantly higher concentration of plasma nitrite/nitrate and a higher median fold-change in iNOS mRNA gene expression. Genotyping of the promoter region showed three different variations: A pentanucleotide repeat (CCTTT) n, -1026T > G (rs2779249) and a novel variant -1153T > A. These variants were associated with increased levels of plasma nitrite/nitrate across all disease stages. The higher expression of iNOS mRNA and plasma nitrite/nitrate among women with pre-cancerous lesions suggests a role for nitric oxide in the natural history of cervical cancer.
宫颈癌是由高危型人乳头瘤病毒（HR-HPV）感染引起的。诱导型一氧化氮合酶（iNOS）是一种参与慢性炎症的可溶性因子，可能会调节HPV感染女性患宫颈癌的风险。本研究的目的是测量不同分级的宫颈病变和宫颈癌女性血浆中亚硝酸盐/硝酸盐水平，并将其与iNOS mRNA的组织特异性表达进行关联分析。收集了120例患有宫颈肿瘤或癌症（非典型鳞状细胞、低度鳞状上皮内病变、高度鳞状上皮内病变和浸润癌）的女性以及35例无宫颈异常的女性的组织活检样本和血浆样本。测量了同一研究对象活检样本中的诱导型一氧化氮合酶（iNOS）mRNA以及血浆中亚硝酸盐/硝酸盐水平。对iNOS基因启动子区域和第16外显子中的Ser608Leu（rs2297518）进行了单核苷酸多态性（SNP）分析。使用线性和逻辑回归分析比较了不同疾病阶段iNOS基因表达和血浆亚硝酸盐/硝酸盐水平的差异。与正常对照组相比，被诊断为高度鳞状上皮内病变或浸润癌的女性血浆亚硝酸盐/硝酸盐浓度显著更高，iNOS mRNA基因表达的中位数变化倍数也更高。启动子区域的基因分型显示出三种不同的变异：一个五核苷酸重复序列（CCTTT）n、-1026T>G（rs2779249）和一个新的变异-1153T>A。这些变异与所有疾病阶段血浆亚硝酸盐/硝酸盐水平升高有关。癌前病变女性中iNOS mRNA和血浆亚硝酸盐/硝酸盐的高表达表明一氧化氮在宫颈癌自然病程中发挥作用。
