Abstract
BackgroundThe mechanistic basis for relapsed hepatocellular carcinoma (HCC) remains poorly understood. Recent research has highlighted the important roles of long non-coding RNAs (lncRNAs) in HCC. However, there are only a few studies on the association between lncRNAs and HCC relapse.MethodsDifferentially expressed lncRNAs and mRNAs between a primary HCC group and relapsed HCC group were identified using the edge R package to analyze the GSE101432 dataset. The differentially expressed lncRNAs and mRNAs were used to construct a lncRNA–mRNA co-expression network. Weighted gene co-expression network analysis followed by Gene Ontology (GO) enrichment analyses were conducted on the database. Furthermore, correlation and survival analyses were performed using The Cancer Genome Atlas database, and expression in the clinical samples was verified by qRT-PCR. Thereafter, we inputted the genes from the two groups into the HCC TNM stage and tumor grade database from TCGA. Finally, we performed Kaplan–Meier survival analysis on the lncRNAs related to relapsed HCC.ResultsIn this study, lncRNAs and mRNAs associated with HCC relapse were identified. Two gene modules were found to be closely linked to this. The GO terms in the yellow and black modules were related to cell proliferation, differentiation, and survival, as well as some transcription-related biological processes. Through qRT-PCR, we found that the expression levels of LINC00941 and LINC00668 in relapsed HCC were higher than those in primary HCC. Further, mRNA levels of LOX, OTX1, MICB, NDUFA4L2, BAIAP2L2, and KCTD17 were changed in relapsed HCC compared to levels in primary HCC. In addition, we verified that these genes could predict the overall survival and recurrence-free survival of HCC. Moreover, we found that LINC00668 and LINC00941 could affect tumor grade and TNM stages. In total, we identified and validated two lncRNAs (LINC00941 and LINC00668) and six mRNAs (LOX, MICB, OTX1, BAIAP2L2, KCTD17, NDUFA4L2) associated with HCC relapse.ConclusionIn summary, we identified the key gene modules and central genes associated with relapsed HCC and constructed lncRNA–mRNA networks related to this. These genes are likely to have potential prognostic value for relapsed HCC and might shed new light on novel biomarkers or diagnostic targets for relapsed HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer in the world [1]
The top 10 Gene Ontology (GO) terms of the DE mRNAs coexpressed with the specific upregulated long non-coding RNAs (lncRNAs) were identified using the KOBAS 2.0 server (Figure 4B)
We obtained the top three DE lncRNAs and coexpressed mRNAs that were upregulated in relapsed tumor and that were expressed in the primary and relapsed tumors and benign adjacent tissue (Figure 4D)
Summary
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer in the world [1]. We aimed to explore the mechanism of HCC relapse and search for prognosis-associated long non-coding RNAs (lncRNAs), which are of great significance as they provide useful information for the diagnosis and prognosis of HCC. An expanding body of evidence shows that lncRNAs modulate gene expression at multiple levels through many complex mechanisms. In addition to their well-established role as regulators of transcription, lncRNAs are effective regulators of pre-mRNA splicing, mRNA decay, and translation [4]. The mechanistic basis for relapsed hepatocellular carcinoma (HCC) remains poorly understood. Recent research has highlighted the important roles of long non-coding RNAs (lncRNAs) in HCC. There are only a few studies on the association between lncRNAs and HCC relapse
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