Comprehensive analysis of a competitiveendogenous RNA network reveals RNAs related to pathologicalfeatures in kidney renal papillary cell carcinoma

Introduction: Kidney cancer (KC) has become a commonlydiagnosed cancer type worldwide which originates from theurinary tubule epithelial system of the renal parenchyma. Thekidney renal papillary cell carcinoma (KIRP) is a relatively raretype of KC that accounts for ۱۵–۲۰% of all kidney malignancies.Since KIRP is considered as a heterogeneous disease in theaspects of cancer progression and patients’ survival outcomes,identification of its molecular mechanisms is critical for bothbasic and clinical research of KIRP, to prevent its early onsetand progression and develop novel and effective diagnostic/prognostic biomarkers. competitive endogenous RNA (ceRNA)hypothesis describes the competitive activity of RNAs for commonbinding sites of target miRNAs, thus forming a ceRNAnetwork which dysregulation of its components is associatedwith different aspects of tumorigenesis. In the present study,we aimed to clarify the relationship of ceRNA elements withpathological features of KIRP by construction of a regulatoryceRNA network.Methods: KIRP RNA-Seq and clinical data were obtained fromThe Cancer Genome Atlas (TCGA) containing ۲۸۳ tumor and۳۲ adjacent non-tumor kidney tissue samples. According to thepathological data, there were ۱۲ patients with and ۲۷۱ patientswithout distant metastasis. In addition, there were ۲۴ patientswith and ۲۵۹ patients without lymph node metastases and therewere ۲۱۷ patients with stages I–II and ۶۶ patients with stagesIII–IV. Differentially-expressed RNAs (DERs) including: lncRNAs(DELs), miRNAs (DEmiRs), and mRNAs (DEMs) in tumorcompared to non-tumor samples were extracted with theR-package DESeq۲ by setting the |log۲ fold change|> ۱ and adjustedp < ۰.۰۱ as the cutoffs. The association between DERs’expressions and distant metastases, lymphatic metastases andstages were defined using a chi-square test, which was basedon the median. Then, the intersections of those DERs showingsignificant association with above-mentioned phenotypes wereretrieved for further analysis. The DIANA-LncBase v۳.۰ wasused to match DELs and DEmiRs. DEmiRs targeting DEMswere predicted using miRTarBase, TarBase, and miRDB. Subsequently,the interaction between DEmiRs and DELs/DEMswas integrated to construct a ceRNA network followed by enrichmentanalysis using the Enrichr tool.Results: We identified ۴۱۱۵ DELs, ۳۸۷ DEmiRs, and ۵۰۹۵DEMs between KIRP tumor and non-tumor tissues. Totally, ۸۰DELs, ۱۵ DEmiRs, and ۳۱۴ DEMs were shared among DERswith significant associations with distant metastases, lymphaticmetastases and stages. By predicting lncRNA–miRNAand miRNA-mRNA interaction pairs, we constructed a ceRNAnetwork that contained ۱۱ lncRNAs, ۵ miRNAs, and ۱۳۹ mRNAs.Finally, the functional enrichment analyses of the ceRNAnetwork revealed that genes were remarkably associated withcancer-related pathways such as Cell cycle, Transcriptionalmisregulation in cancer, Pathways in cancer, Cell adhesionmolecules and Wnt signaling pathway.Conclusion: In Conclusion: , we constructed a ceRNA networkwith KIRP-specific lncRNAs, mRNAs, and miRNAs, and investigatedtheir correlations with pathological features. Our findings provide novel insight into a better understanding ofthe ceRNA network and potential biomarkers in KIRP, althoughtheir feasibility as diagnosis or prognosis biomarkers should befurther investigated.

کلیدواژه ها:

Non-coding RNAs ، Systems Biology