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MicroRNA dysregulation as a prognostic biomarker in colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the most potentially curable cancers, yet it remains the fourth most common overall cause of cancer death worldwide. The identification of robust molecular prognostic biomarkers can refine the conventional tumor-node-metastasis staging system, avoid understaging of tumor, and help pinpoint patients with early-stage CRC who may benefit from aggressive treatments. Recently, epigenetic studies have provided new molecular evidence to better categorize the CRC subtypes and predict clinical outcomes. In this review, we summarize recent findings concerning the prognostic potential of microRNAs (miRNAs) in CRC. We first discuss the prognostic value of three tissue miRNAs (miR-21-5p, miR-29-3p, miR-148-3p) that have been examined in multiple studies. We also summarize the dysregulation of miRNA processing machinery DICER in CRC and its association with risk for mortality. We also reviewe the potential application of miRNA-associated single-nucleotide polymorphisms as prognostic biomarkers for CRC, especially the miRNA-associated polymorphism in the KRAS gene. Last but not least, we discuss the microsatellite instability-related miRNA candidates. Among all these candidates, miR-21-5p is the most promising prognostic marker, yet further prospective validation studies are required before it can go into clinical usage.

SUBMITTER: Dong Y

PROVIDER: S-EPMC4206254 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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MicroRNA dysregulation as a prognostic biomarker in colorectal cancer.

Dong Yujuan Y Yu Jun J Ng Simon Sm SS

Cancer management and research 20141014

Colorectal cancer (CRC) is one of the most potentially curable cancers, yet it remains the fourth most common overall cause of cancer death worldwide. The identification of robust molecular prognostic biomarkers can refine the conventional tumor-node-metastasis staging system, avoid understaging of tumor, and help pinpoint patients with early-stage CRC who may benefit from aggressive treatments. Recently, epigenetic studies have provided new molecular evidence to better categorize the CRC subtyp ...[more]

PMID: 25342918

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Project description:Mounting evidence has demonstrated that a lot of miRNAs are overexpressed or downregulated in colorectal cancer (CRC) tissues and play a crucial role in tumorigenesis, invasion, and migration. The aim of our study was to screen new biomarkers related to CRC prognosis by bioinformatics analysis. By using the R language edgeR package for the differential analysis and standardization of miRNA expression profiles from The Cancer Genome Atlas (TCGA), 502 differentially expressed miRNAs (343 up-regulated, 159 down-regulated) were screened based on the cut-off criteria of p < 0.05 and |log2FC|>1, then all the patients (421) with differentially expressed miRNAs and complete survival time, status were then randomly divided into train group (212) and the test group (209). Eight miRNAs with p < 0.005 were revealed in univariate cox regression analysis of train group, then stepwise multivariate cox regression was applied for constituting a five-miRNA (hsa-miR-5091, hsa-miR-10b-3p, hsa-miR-9-5p, hsa-miR-187-3p, hsa-miR-32-5p) signature prognostic biomarkers with obviously different overall survival. Test group and entire group shown the same results utilizing the same prescient miRNA signature. The area under curve (AUC) of receiver operating characteristic (ROC) curve for predicting 5 years survival in train group, test group, and whole cohort were 0.79, 0.679, and 0.744, respectively, which demonstrated better predictive power of prognostic model. Furthermore, Univariate cox regression and multivariate cox regression considering other clinical factors displayed that the five-miRNA signature could serve as an independent prognostic factor. In order to predict the potential biological functions of five-miRNA signature, target genes of these five miRNAs were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway and Gene Ontology (GO) enrichment analysis. The top 10 hub genes (ESR1, ADCY9, MEF2C, NRXN1, ADCY5, FGF2, KITLG, GATA1, GRIA1, KAT2B) of target genes in protein protein interaction (PPI) network were screened by string database and Cytoscape 3.6.1 (plug-in cytoHubba). In addition, 19 of target genes were associated with survival prognosis. Taken together, the current study showed the model of five-miRNA signature could efficiently function as a novel and independent prognosis biomarker and therapeutic target for CRC patients.

Project description:BackgroundColorectal cancer (CRC) is one of the leading causes of cancer death worldwide. microRNAs (miRNAs) repress gene expression by binding to complementary sequences in the 3' untranslated region (3'UTR) of target mRNAs. Alternative polyadenylation (APA) are relevant to the variability of the 3'UTR of mRNA. However, the posttranscriptional dysregulation of miRNAs and APA in CRC are poorly understood.MethodIn this study, we conducted small RNA sequencing to identify differentially expressed miRNAs (DERs) and their target genes. Function analysis on DER-target genes can explain the regulation roles of miRNAs in CRC. The mutual regulation of miRNAs and APA was analyzed by combining miRNA data to 3'UTR alteration using 3' termini of polyadenylated RNAs sequencing (3T-seq) technique, and this was validated using TCGA gene expression data.ResultsOur results showed 64 significant differentially expressed miRNAs (DERs) in CRC patients. Their target genes were related to cell adhesion and transcription regulation and were prevailingly involved in the CRC-related pathway. Integrative analysis of the miRNA and APA profile revealed 16 DERs were correlated with 12 polyadenylation factors, and six of them were significantly differently expressed in CRC. We also found four DERs that lost binding sites due to APA and showed a positive correlation between the miRNA and gene expression.ConclusionOur study found that miRNAs regulated APA by modulating key polyadenylation factors, and several miRNAs lost their suppression on mRNA due to APA. Associating this with gene expression may provide some important clues for a deeper study of posttranscriptional cellular regulation and biomarker research in CRC. Our data provided the first evidence that the interaction between miRNAs and APA associated with gene expression could serve as biomarkers for CRC, suggesting that hsa-miR-133a-3p and MLEC, hsa-miR-145-5p and SET, hsa-miR-1-3p and PPIA, and hsa-miR-378d and YY1 might be novel and potential biomarkers in improving the diagnosis of CRC.

Project description:Background: Colorectal cancer (CRC) is one of the most common malignant tumors and has high morbidity and mortality rates. Previous studies have shown that TSPEAR mutations are involved in the development and progression of gastric cancer and liver cancer. However, the role of TSPEAR in CRC is still unclear. Methods: In The Cancer Genome Atlas (TCGA) database, 590 CRC patients with complete survival information were analyzed. We assessed TSPEAR expression in a pan-cancer dataset from the TCGA database. Cox regression analysis was performed to evaluate factors associated with prognosis. Enrichment analysis via the R package "clusterProfiler" was used to explore the potential function of TSPEAR. The single-sample GSEA (ssGSEA) method from the R package "GSVA" and the TIMER database were used to investigate the association between the immune infiltration level and TSPEAR expression in CRC. The R package "maftools" was used to explore the association between tumour mutation burden (TMB) and TSPEAR expression in CRC. CCK-8 assays and cell invasion assays were used to detect the effect of TSPEAR and TGIF2 on the biological behavior of CRC cells. Results: Pan-cancer analysis revealed that TSPEAR was upregulated in CRC tissues compared to normal tissues and that high TSPEAR expression was associated with poorer overall survival (OS) (p=0.0053). The expression of TSPEAR increased with increasing TNM stage, T stage, N stage, and M stage. The nomogram constructed with TSPEAR, age, and TNM stage showed better predictive value than TSPEAR, age, or TNM stage alone. Immune cell infiltration analysis revealed that high expression of TSPEAR was associated with lower immune cell infiltration. Tumor mutation burden (TMB) analysis indicated that high expression of TSPEAR was associated with lower TMB (p=0.005), and high TMB was associated with shorter OS (p=0.02). CCK-8 assays and cell invasion assays indicated that in vitro knockdown of TSPEAR inhibited the proliferation, migration, and invasion of CRC cells. In addition, TSPEAR expression may be regulated by the upstream transcription factor TGIF2. Conclusion: TSPEAR expression was higher in CRC tissues than in normal tissues. Its upregulation was significantly associated with a poor prognosis. Additionally, TSPEAR plays a significant role in tumor immunity and the biological behavior of CRC cells. Thus, TSPEAR may become a promising prognostic biomarker and therapeutic target for CRC patients.

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MicroRNA dysregulation as a prognostic biomarker in colorectal cancer.

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MicroRNA dysregulation as a prognostic biomarker in colorectal cancer.

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