Biological and clinical relevance of correlated expression levels of coding and long noncoding RNAs in HPV16 positive cervical cancers.

IF 3.8 3区 医学 Q2 GENETICS & HEREDITY
Abhisikta Ghosh, Abarna Sinha, Arnab Ghosh, Somrita Roy, Sumana Mallick, Vinoth Kumar, Sonia Mathai, Jaydip Bhaumik, Asima Mukhopadhyay, Saugata Sen, Aditi Chandra, Arindam Maitra, Nidhan K Biswas, Partha P Majumder, Sharmila Sengupta
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Abstract

Human papillomavirus (HPV) drives cervical cancer (CaCx) pathogenesis and viral oncoproteins jeopardize global gene expression in such cancers. In this study, our aim was to identify differentially expressed coding (DEcGs) and long noncoding RNA genes (DElncGs) specifically sense intronic and Natural Antisense Transcripts as they are located in the genic regions and may have a direct influence on the expression pattern of their neighbouring coding genes. We compared HPV16-positive CaCx patients (N = 44) with HPV-negative normal individuals (N = 34) by employing strand-specific RNA-seq and determined the relationships between DEcGs and DElncGs and their clinical implications. By performing Gene set enrichment and protein-protein interaction (PPI) analyses of DEcGs, we identified enrichment of processes crucial for abortive virus life cycle and cancer progression. The DEcGs formed 16 gene clusters which we identified through Molecular Complex Detection (MCODE) plugin of Cytoscape. All the gene clusters portrayed cancer-related functions. We recorded significantly correlated expression levels of 79 DElncGs with DEcGs at proximal genomic loci based on Pearson's Correlation coefficients. Of these gene pairs, 24 pairs portrayed significantly altered correlation coefficients among patients, compared to normal individuals. Of these, 6 DEcGs of 6 such gene pairs, belonged to 5 of the identified gene clusters, one of which was survival-associated. Out of the 24 correlated DEcG: DElncG pairs, we identified 3 pairs, where expression of both members was significantly associated with patient overall survival. The findings justify the cooperative roles of these gene pairs, in patient prognostication, thereby bearing immense potential for translation. Thus, elucidation of correlative strengths between paired DElncGs and DEcGs in patient and normal samples, could serve as a foundation for identification of therapeutic and prognostic targets of HPV16-positive CaCx.

HPV16 阳性宫颈癌中编码和长非编码 RNA 相关表达水平的生物学和临床意义。
人类乳头瘤病毒(HPV)是宫颈癌(CaCx)的致病因素,而病毒癌蛋白会危及此类癌症的全局基因表达。在这项研究中,我们的目的是识别差异表达的编码基因(DEcGs)和长非编码 RNA 基因(DElncGs),这些基因特异性地感知内含子和天然反义转录本,因为它们位于基因区,可能直接影响邻近编码基因的表达模式。我们通过链特异性 RNA-seq,比较了 HPV16 阳性的 CaCx 患者(44 人)和 HPV 阴性的正常人(34 人),确定了 DEcGs 和 DElncGs 之间的关系及其临床意义。通过对DEcGs进行基因组富集和蛋白-蛋白相互作用(PPI)分析,我们发现了对中止病毒生命周期和癌症进展至关重要的富集过程。通过Cytoscape的分子复合体检测(MCODE)插件,我们发现DEcGs形成了16个基因簇。所有基因簇都具有癌症相关功能。根据皮尔逊相关系数,我们记录了79个DElncGs与DEcGs在近端基因组位点上的明显相关表达水平。在这些基因对中,与正常人相比,24对基因对在患者中的相关系数有明显变化。其中,6 个基因对中的 6 个 DEcGs 属于 5 个已确定的基因簇,其中一个与生存相关。在 24 个相关的 DEcG:DElncG 对中,我们发现有 3 对基因对的两个成员的表达都与患者的总生存期显著相关。这些发现证明了这些基因对在患者预后中的合作作用,因此具有巨大的转化潜力。因此,阐明患者和正常样本中成对 DElncGs 和 DEcGs 之间的相关性,可以为确定 HPV16 阳性 CaCx 的治疗和预后靶点奠定基础。
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来源期刊
Human Genomics
Human Genomics GENETICS & HEREDITY-
CiteScore
6.00
自引率
2.20%
发文量
55
审稿时长
11 weeks
期刊介绍: Human Genomics is a peer-reviewed, open access, online journal that focuses on the application of genomic analysis in all aspects of human health and disease, as well as genomic analysis of drug efficacy and safety, and comparative genomics. Topics covered by the journal include, but are not limited to: pharmacogenomics, genome-wide association studies, genome-wide sequencing, exome sequencing, next-generation deep-sequencing, functional genomics, epigenomics, translational genomics, expression profiling, proteomics, bioinformatics, animal models, statistical genetics, genetic epidemiology, human population genetics and comparative genomics.
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