Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common lethal liver cancer worldwide. Currently, despite the latest developments in genomics and transcriptomics for ICC in recent years, the molecular pathogenesis promoting ICC remains elusive, especially in regulatory mechanisms of long noncoding RNAs (lncRNAs), which acts as competing endogenous RNA (ceRNA). In order to elucidate the molecular mechanism of functional lncRNA, expression profiles of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) were obtained from The Cancer Genome Atlas (TCGA) database and an integrative analysis of the ICC-associated ceRNA network was performed. Moreover, gene oncology enrichment analyses for the genes in the ceRNA network were implemented and novel prognostic biomarker lncRNA molecules were identified. In total, 6,738 differentially expressed mRNAs (DEmRNAs), 2,768 lncRNAs (DElncRNAs), and 173 miRNAs (DEmiRNAs) were identified in tumor tissues and adjacent nontumor ICC tissues with the thresholds of adjusted P < 0.01 and |logFC| > 2. An ICC-specific ceRNA network was successfully constructed with 30 miRNAs, 16 lncRNAs, and 80 mRNAs. Gene oncology enrichment analyses revealed that they were associated with the adaptive immune response, T cell selection and positive regulation of GTPase activity categories. Among the ceRNA networks, DElncRNAs ARHGEF26-AS1 and MIAT were found to be hub genes in underexpressed and overexpressed networks, respectively. Notably, univariate Cox regression analysis indicated that DElncRNAs HULC significantly correlated with overall survival (OS) in ICC patients (P value < 0.05), and an additional survival analysis for HULC was reconfirmed in an independent ICC cohort from the Gene Expression Omnibus (GEO) database. These findings contribute to a more comprehensive understanding of the ICC-specific ceRNA network and provide novel strategies for subsequent functional studies of lncRNAs in ICC.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is the second most common lethal liver cancer worldwide [1]
We identified a total of 6738 differentially expressed mRNAs (DEmRNAs), 2768 DElncRNAs, and 173 DEmiRNAs in tumor tissues and adjacent nontumor ICC tissues using the “edgeR” package with the thresholds of P < 0.01 and |log FC| > 2
We found 4164 (61.80%) upregulated and 2574 (38.20%) downregulated DEmRNAs, 2028 (73.27%) upregulated and 740 (26.73%) downregulated DElncRNAs, and 110 (63.58%) upregulated and 63 (36.42%) downregulated DEmiRNAs between ICC and normal samples (Figure 1(a))
Summary
Intrahepatic cholangiocarcinoma (ICC) is the second most common lethal liver cancer worldwide [1]. Due to the high rate of recurrence in this tumor [3], none of these approaches can significantly prolong long-term survival. Erefore, there is a great need for understanding the specific molecular mechanism of tumors and for the identification of potential molecular biomarkers for ICC diagnosis and treatment. In recent years, accumulating studies have focused on long noncoding RNAs (lncRNA) that are defined as transcripts over 200 nucleotides in length and have indicated that lncRNAs substantially affect gene expression that is dysregulated in numerous cancers. Homeobox transcript antisense intergenic RNA (HOTAIR) was found to facilitate tumorigenesis by promoting phosphatase and tensin homolog (PTEN) methylation [8], and PVT1 binds EZH2 directly to silence ANGPTL4 expression by promoting
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