基于mRNA和miRNA芯片探索影响结直肠癌肝转移的靶基因
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摘要
目的筛选与结直肠癌(CRC)肝转移相关的靶基因。方法从Gene Expressed Omnibus(GEO)数据库下载mRNA和miRNA的表达谱(GSE30687和GSE44121)。通过limma函数包分析得出差异表达mRNA和差异表达miRNA。基于DAVID在线工具进行差异表达mRNA的GO功能富集分析和KEGG通路富集分析。利用TargetScan筛选由差异表达miRNA调节的靶基因,并构建miRNA-mRNA调节网络。结果与原发性CRC样品相比,在具有肝转移的CRC样品中筛选出180个差异表达mRNAs,其中116个表达下调,64个表达上调,另外筛选出15个差异表达miRNAs,表达上调的有6个,表达下调的有9个。差异表达mRNAs富集于32个GO terms中,如阴离子运输、细胞的顶端部分、脱氧核糖核酸酶活性等。另外,这些差异表达mRNAs主要富集在包括类固醇生物合成和霍乱弧菌感染在内的2条通路中。miRNA-mRNA调控网络包括50个miRNA-mRNA关系对,其中具有较高节点度的基因为纤连蛋白1(FN1)和骨髓嗜病毒整合位点1(MEIS1)。结论 FN1和MEIS1基因可能是大肠癌肝转移的潜在生物标志物。
Objective To screen target genes related to liver metastasis in colorectal cancer(CRC).MethodsThe mRNA and miRNA expression profiles(GSE30687 and GSE44121) were downloaded from the Gene Expressed Omnibus(GEO) database. The differentially expressed genes(DEGs) and differentially expressed miRNAs(DEMs) were identified through the limma software package, respectively. The database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathwayenrichment analysis of DEGs. Targets regulated by DEMs were screened by TargetScan, and the miRNA-mRNA regulatednetwork was constructed.ResultsCompared with non-metastatic CRC samples, there were 180 mRNAs and 15 miRNAs inDEMs in CRC samples with liver metastasis, respectively. DEGs were enriched in 32 GO terms and 2 KEGG pathways. In 50 miRNA-mRNA pairs involved in the miRNA-mRNA network, there were genes with higher node degrees including FN1 andMEIS1.Conclusion FN1 and MEIS1 genes might be potential biomarkers of CRC with liver metastasis.
Objective To screen target genes related to liver metastasis in colorectal cancer(CRC).MethodsThe mRNA and miRNA expression profiles(GSE30687 and GSE44121) were downloaded from the Gene Expressed Omnibus(GEO) database. The differentially expressed genes(DEGs) and differentially expressed miRNAs(DEMs) were identified through the limma software package, respectively. The database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathwayenrichment analysis of DEGs. Targets regulated by DEMs were screened by TargetScan, and the miRNA-mRNA regulatednetwork was constructed.ResultsCompared with non-metastatic CRC samples, there were 180 mRNAs and 15 miRNAs inDEMs in CRC samples with liver metastasis, respectively. DEGs were enriched in 32 GO terms and 2 KEGG pathways. In 50 miRNA-mRNA pairs involved in the miRNA-mRNA network, there were genes with higher node degrees including FN1 andMEIS1.Conclusion FN1 and MEIS1 genes might be potential biomarkers of CRC with liver metastasis.
引文
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[30]Mohr S,Doebele C,Comoglio F,et al.Hoxa9 and Meis1cooperatively induce addiction to syk signaling by suppressing miR-146a in acute myeloid leukemia[J].Cancer Cell,2017,31(4):549-562.doi:10.1016/j.ccell.2017.03.001.
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[2]Siegel RL,Miller KD,Jemal A.Cancer statistics,2019[J].CA:CANCER J Clin,2019,69(1):7-34.doi:org/10.3322/caac.21551.
[3]Song N,Shin A,Park JW,et al.Common risk variants for colorectal cancer:an evaluation of associations with age at cancer onset[J].Sci Rep,2017,7:40644.doi:10.1038/srep40644.
[4]Chorti A,Bangeas P,Papavramidis TS,et al.Role of MicroRNA in the diagnosis and therapy of hepatic metastases from colorectal cancer[J].MicroRNA,2018,7(3):167-177.doi:org/10.2174/2211536607666180525073302.
[5]Engstrand J,Nilsson H,Str?mberg C,et al.Colorectal cancer liver metastases-a population-based study on incidence,management and survival[J].BMC Can,2018,18(1):78.doi:org/10.1186/s12885-017-3925-x.
[6]Norén A,Sandstr?m P,Gunnarsdottir K,et al.Identification of inequalities in the selection of liver surgery for colorectal liver metastases in sweden[J].Scand J Surg,2018,107(4):145749691876670.doi:10.1177/1457496918766706.
[7]葛少华,孔凡萍,邓正明,等.自拟健脾补肾方对结直肠癌肝转移患者血清MMP-9、TIMP-1的影响[J].肿瘤药学,2018,8(4):569-573.Ge SH,Kong FP,Deng ZM,et al.Effects of jianpi bushen recipe on serum MMP-9 and TIMP-1 levels in patients with liver metastases from colorectal cancer[J].Anti-tumor Pharmacy,2018,8(4):569-573.doi:10.3969/j.issn.2095?1264.2018.04.18.
[8]Nedaeinia R,Sharifi M,Avan A,et al.Inhibition of microRNA-21via locked nucleic acid-anti-miR suppressed metastatic features of colorectal cancer cells through modulation of programmed cell death 4[J].Tumor Biol,2017,39(3):1010428317692261.doi:10.1177/1010428317692261.
[9]Barrett T,Wilhite SE,Ledoux P,et al.NCBI GEO:archive for functional genomics data sets-update[J].Nucleic Acids Res,2012,41(D1):D991-D995.doi:10.1093/nar/gks1193.
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[12]Shi Y,Yang F,Wei S,et al.Identification of key genes affecting results of hyperthermia in osteosarcoma based on integrative ChIP-Seq/TargetScan analysis[J].Med Sci Monit,2017,23:2042-2048.doi:10.12659/MSM.901191.
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[19]Reddy BS.Diet and colon cancer:evidence from human and animal model studies[M].Diet,nutrition and cancer:a critical evaluation.Boca Raton.CRC Press,2018:47-66.
[20]Song EM,Byeon JS,Lee SM,et al.Fecal fatty acid profiling as a potential new screening biomarker in patients with colorectal cancer[J].Dig Dis Sci,2018,63(5):1229-1236.doi:10.1007/s10620-018-4982-y.
[21]Gilligan LC,Ali G,Vivien T,et al.Estrone sulfate transport and steroid sulfatase activity in colorectal cancer:implications for hormone replacement therapy[J].Front Pharmacol,2017,7(8):103.doi:10.3389/fphar.2017.00103.
[22]Roth U,Razawi H,Hommer J,et al.Differential expression proteomics of human colorectal cancer based on a syngeneic cellular model for the progression of adenoma to carcinoma[J].Proteomics,2010,10(2):194-202.doi:10.1002/pmic.200900614.
[23]Lin J,Zee RYL,Liu KY,et al.Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women[J].Cancer Causes&Control,2010,21(6):897-908.doi:10.1007/s10552-010-9518-5.
[24]Padukone S,Mandal J,Parija SC.Severe Blastocystis subtype 3infection in a patient with colorectal cancer[J].Trop Parasitol,2017,7(2):122-124.doi:10.4103/tp.TP_87_15.
[25]曹燕青,王希成,莫凯岚,等.乙肝病毒感染对不同部位结直肠癌肝转移发生率的影响[J].临床医学工程,2017,24(12):1689-1690.Cao YQ,Wang XC,Mo KL,et al.Effect of hepatitis b virus infection on the incidence of liver metastasis of colorectal cancer with different primary locations[J].Clin Med Engi,2017,24(12):1689-1690.doi:10.3969/j.issn.1674-4659.2017.12.1689.
[26]Morita Y,Hata K,Nakanishi M,et al.Cellular fibronectin 1promotes VEGF-C expression,lymphangiogenesis and lymph node metastasis associated with human oral squamous cell carcinoma[J].Clin Exp Metastasis,2015,32(7):739-753.doi:10.1007/s10585-015-9741-2.
[27]Wu J,Wang Y,Xu X,et al.Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer[J].Carcinogenesis,2016,37(5):511-521.doi:10.1093/carcin/bgw029.
[28]Cai X,Liu C,Zhang TN,et al.Down-regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation,migration and invasion[J].J Cell Biochem,2018,119(6):4717-4728.doi:10.1002/jcb.26651.
[29]Xu X,Liu Z,Zhou L,et al.Characterization of genome-wide TFCP2 targets in hepatocellular carcinoma:implication of targets FN1 and TJP1 in metastasis[J].J Exp Clin Cancer Res,2015,34(1):6.doi:10.1186/s13046-015-0121-1.
[30]Mohr S,Doebele C,Comoglio F,et al.Hoxa9 and Meis1cooperatively induce addiction to syk signaling by suppressing miR-146a in acute myeloid leukemia[J].Cancer Cell,2017,31(4):549-562.doi:10.1016/j.ccell.2017.03.001.
[31]Crist RC,Roth JJ,Waldman SA,et al.A conserved tissue-specific homeodomain-less isoform of MEIS1 is downregulated in colorectal cancer[J].PLoS One,2011,6(8):e23665.doi:10.1371/journal.pone.0023665.