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Screening candidate microRNA-mRNA regulatory pairs for predicting the response to chemoradiotherapy in rectal cancer by a bioinformatics approach.

ABSTRACT: Extensive efforts have been undertaken in search of biomarkers for predicting the chemoradiotherapy response in rectal cancer. However, most attention on treatment efficiency prediction in carcinoma is addicted to single or limited molecules. Network biomarkers are considered to outperform single molecules in predictive power. In this study, candidate microRNAs (miRNAs) were identified from the PubMed citations and miRNA expression profiles. Targets of miRNAs were obtained from four experimentally confirmed interactions and three computationally predicted databases. Functional enrichment analysis of all the targets revealed their associations with chemoradiotherapy response, indicating they could be promising biomarkers. Two lists of key target mRNAs of the candidate miRNAs were retrieved from protein-protein interaction (PPI) network and mRNA expression profiles, respectively. Pathway analysis and literature validation revealed that the mRNA lists were highly related to the ionizing radiation. The above miRNAs along with the key miRNA targets provide potential miRNA-mRNA regulatory pairs as network biomarkers in which all the network components may be used for predicting the chemoradiotherapy response. These results demonstrated that the network biomarkers could provide a useful model for predicting the chemoradiotherapy response and help in further understanding the molecular basis of response differences, which should be prioritized for further study.

SUBMITTER: Peng Q

PROVIDER: S-EPMC5595906 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Screening candidate microRNA-mRNA regulatory pairs for predicting the response to chemoradiotherapy in rectal cancer by a bioinformatics approach.

Peng Qiliang Q Zhu Junjia J Shen Peipei P Yao Wenyan W Lei Yu Y Zou Li L Xu Yingying Y Shen Yuntian Y Zhu Yaqun Y

Scientific reports 20170912 1

Extensive efforts have been undertaken in search of biomarkers for predicting the chemoradiotherapy response in rectal cancer. However, most attention on treatment efficiency prediction in carcinoma is addicted to single or limited molecules. Network biomarkers are considered to outperform single molecules in predictive power. In this study, candidate microRNAs (miRNAs) were identified from the PubMed citations and miRNA expression profiles. Targets of miRNAs were obtained from four experimental ...[more]

PMID: 28900297

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Project description:Neoadjuvant chemoradiotherapy (nCRT) following surgery significantly improves the survival rate of patients with rectal cancer. However, nCRT is associated with significant adverse symptoms and high medical costs. Therefore, it is important to investigate potential biomarkers for the prediction of the response to nCRT in patients with rectal cancer. The present study identified candidate biomarkers for predicting a complete response (CR) to nCRT in patients with rectal cancer and investigated the associated mechanisms. Microarray data (accession no. GSE29298) was downloaded from the Gene Expression Omnibus database. Differentially expressed microRNAs (miRNAs/miR) were screened between the pathological CR (pCR) group and no pCR (incomplete response) group. miRNA target genes were predicted using the miRWalk 2.0 online tool and subjected to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Furthermore, a miRNA co‑regulatory network was constructed and disease‑associated genes were predicted. The results demonstrated that a total of 36 upregulated and 5 downregulated miRNAs were identified between the two groups. Among these differentially expressed miRNAs, miR‑548c‑5p, miR‑548d‑5p and miR‑663a were significantly associated with a CR to nCRT. The co‑regulatory network and pathway analysis indicated that miR‑548c‑5p and miR‑548d‑5p may function together through stem cell pluripotency and ubiquitin‑mediated proteolysis signaling pathways. Furthermore, the prediction of disease‑associated genes demonstrated that miR‑548c‑5p/miR‑548d‑5p and miR‑663a may regulate genes associated with rectal cancer, including mutated in colorectal cancers (MCC) and adenomatous polyposis coli (APC), and colorectal neoplasms, including interleukin‑6 signal transducer (IL6ST), cell cycle checkpoint kinase 2 (CHEK2), marker of proliferation Ki‑67 (MKI67), cadherin 7 (CDH7), calreticulin (CALR) and transforming growth factor β1 (TGFB1). Therefore, miR‑548c‑5p, miR‑548d‑5p and miR‑663a are promising candidate biomarkers for predicting a CR to nCRT. miR‑548c‑5p/miR‑548d‑5p may be associated with a CR by regulating IL6ST, CHEK2, MKI67 and MCC. In addition, it may function through the pluripotency of stem cells and ubiquitin‑mediated proteolysis signaling pathways. miR‑663a may be associated with a CR to nCRT by targeting CDH7, CALR, APC and TGFβ1. Thus, the miRNA biomarkers investigated in the present study may represent novel therapeutic targets for the prediction and eventual improvement of the response to nCRT in patients with rectal cancer.

Project description:The incorporation of chemoradiation prior to resection of the tumour has revolutionized the management of locally advanced rectal cancer. However, a large proportion of these patients are resistant to preoperative treatment schedule. We recently reported that c-Myc gene expression correlates negatively with this resistance in patients with rectal cancer. In this study, we carried out integrated analysis of miRNA and mRNA expression profiling in 45 pre-treatment rectal tumour. Further, expression of miRNAs and c-Myc, and their relationship with clinicopathological factors and patient survival was analysed. As a result, we found that 12 miRNAs were differentially expressed between responder and non-responder rectal cancer patients. Functional classification revealed an association between differentially expressed miRNAs and c-Myc. Subsequent quantitative real-time PCR results showed that both, miRNA-148 and miRNA-375 levels were significantly lower in responder compared to non-responder patients. Notably, the higher level of miRNA-375 was significantly negatively correlated with c-Myc. These results suggest that miRNA-375 and its targeted c-Myc play an important role as predictive biomarker of response to neoadjuvant treatment in patients with locally advanced rectal cancer, but still not suitable for prognosis. Pre-treatment biopsies of 22 patients with LARC were prospectively collected and freshly frozen according to an institutional board-approved protocol. Tumour response was assessed in surgical specimens by pathological examination based on the semi-quantitative tumour regression grading (TRG) system described by Mandard in 1994[36]: TRG1 and TRG2 scores were considered responders, whereas TRG3, TRG4, and TRG5 were classified as non-responders. The inclusion criteria were: histologically proven rectal tumour at a clinical stage UICC II-III (cT3-4/and or N positive), following endorectal ultrasound and/or MRI scan. Patients were excluded if they had the tumour located above 13 cm from the anal verge by rigid rectoscopy, synchronic colonic cancer assessed by colonoscopy, distant metastases by 18FDG PET-CT scan, and suspicion of hereditary colorectal cancer. All patients subsequently received a total dose of 50.4Gy of radiation (28 fractions of 1.8Gy) associated with capecitabine (oral form of 5-FU) with or without oxaliplatine, according to our Hospital Clinical Practice Guidelines. Standardized Surgery was performed, including total mesorectal excision, following an interval of 8-10 weeks after completion of CT/RT.

Project description:BackgroundHazels (Corylus spp.) are economically important nut-producing species in which ovule development determines seed plumpness, one of the key parameters reflecting nut quality. microRNAs (miRNAs) play important roles in RNA silencing and the post-transcriptional regulation of gene expression. However, very little is currently known regarding the miRNAs involved in regulating ovule growth and development.ResultsIn this study, we accordingly sought to determine the important miRNAs involved in ovule development and growth in hazel. We examined ovules at four developmental stages, namely, ovule formation (Ov1), early ovule growth (Ov2), rapid ovule growth (Ov3), and ovule maturity (Ov4). On the basis of small RNA and mRNA sequencing using the Illumina sequencing platform, we identified 970 miRNAs in hazel, of which 766 and 204 were known and novel miRNAs, respectively. In Ov1-vs-Ov2, Ov1-vs-Ov3, Ov1-vs-Ov4, Ov2-vs-Ov3, Ov2-vs-Ov4, and Ov3-vs-Ov4 paired comparisons, 471 differentially expressed microRNAs (DEmiRNAs) and their 3117 target differentially expressed messenger RNAs (DEmRNAs) formed 11,199 DEmiRNA/DEmRNA pairs, with each DEmiRNA changing the expression of an average of 6.62 target mRNAs. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of all DEmRNAs revealed 29 significantly enriched KEGG pathways in the six paired comparisons, including protein export (ko03060), fatty acid elongation (ko00062), starch and sucrose metabolism (ko00500), fatty acid biosynthesis (ko00061), and amino sugar and nucleotide sugar metabolism (ko00520). Our results indicate that DEmiRNA/DEmRNA pairs showing opposite change trends were related to stress tolerance, embryo and seed development, cell proliferation, auxin transduction, and the biosynthesis of proteins, starch, and fats may participate in ovule growth and development.ConclusionsThese findings contribute to a better understanding of ovule development at the level of post-transcriptional regulation, and lay the foundation for further functional analyses of hazelnut ovule growth and development.

Project description:BackgroundLung adenocarcinoma (LUAD) is a common lung cancer with a high mortality, for which microRNAs (miRNAs) play a vital role in its regulation. Multiple messenger RNAs (mRNAs) may be regulated by miRNAs, involved in LUAD tumorigenesis and progression. However, the miRNA-mRNA regulatory network involved in LUAD has not been fully elucidated.MethodsDifferentially expressed miRNAs and mRNA were derived from the Cancer Genome Atlas (TCGA) dataset in tissue samples and from our microarray data in plasma (GSE151963). Then, common differentially expressed (Co-DE) miRNAs were obtained through intersected analyses between the above two datasets. An overlap was applied to confirm the Co-DEmRNAs identified both in targeted mRNAs and DEmRNAs in TCGA. A miRNA-mRNA regulatory network was constructed using Cytoscape. The top five miRNA were identified as hub miRNA by degrees in the network. The functions and signaling pathways associated with the hub miRNA-targeted genes were revealed through Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The key mRNAs in the protein-protein interaction (PPI) network were identified using the STRING database and CytoHubba. Survival analyses were performed using Gene Expression Profiling Interactive Analysis (GEPIA).ResultsThe miRNA-mRNA regulatory network consists of 19 Co-DEmiRNAs and 760 Co-DEmRNAs. The five miRNAs (miR-539-5p, miR-656-3p, miR-2110, let-7b-5p, and miR-92b-3p) in the network were identified as hub miRNAs by degrees (>100). The 677 Co-DEmRNAs were targeted mRNAs from the five hub miRNAs, showing the roles in the functional analyses of the GO analysis and KEGG pathways (inclusion criteria: 836 and 48, respectively). The PPI network and Cytoscape analyses revealed that the top ten key mRNAs were NOTCH1, MMP2, IGF1, KDR, SPP1, FLT1, HGF, TEK, ANGPT1, and PDGFB. SPP1 and HGF emerged as hub genes through survival analysis. A high SPP1 expression indicated a poor survival, whereas HGF positively associated with survival outcomes in LUAD.ConclusionThis study investigated a miRNA-mRNA regulatory network associated with LUAD, exploring the hub miRNAs and potential functions of mRNA in the network. These findings contribute to identify new prognostic markers and therapeutic targets for LUAD patients in clinical settings.

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Screening candidate microRNA-mRNA regulatory pairs for predicting the response to chemoradiotherapy in rectal cancer by a bioinformatics approach.

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Screening candidate microRNA-mRNA regulatory pairs for predicting the response to chemoradiotherapy in rectal cancer by a bioinformatics approach.

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