RNA Language in Colorectal Cancer Using an Integrative Bioinformatics Approach
Gastroenterology and Hepatology from Bed to Bench,
8 March 2021
Background: Identification of competing endogenous RNAs (ceRNAs), especially circRNAs, have become new hotspots in cancer researches. Although, their roles and underlying mechanisms in colorectal cancer (CRC) development remain mostly unknown. The aim of this study was to integrate both coding and non-coding available microarray data in development of CRC coupled with bioinformatics analyses to understand a more inclusive pathobiologic map regarding their molecular interactions and functions.
Methods: The microarray data were retrieved from the Gene Expression Omnibus (GEO) database and analyzed. Several bioinformatics tools and databases including CircInteractome, CSCD, miRTarbBase, TargetScan, miRmap, GEPIA, STRING, Enrichr, DAVID, and MCODE were applied for further elucidation. Principal component analysis (PCA) has seperatly run for four datasets. The dysregulated circRNA-miRNA-mRNA network in CRC was constructed by Cytoscape. In addition, co-expression and protein-protein interaction (PPI) networks were established based on differentially expressed (DE) protein coding genes in CRC.
Results: PCA discloses colorectal tumor and normal tissuses could be distinguished not only by mRNAs expression profile, but also by both circRNAs and miRNAs expression profiles. We identified 14 DE mRNAs (commonly between two datasets), 85 DE miRNAs and 36 DE circRNAs in CRC tissues compared with normal tissues. Taking their potential interactions into account, a circRNA-miRNA-mRNA network was constructed. Then, according to ceRNA hypothesis, the axes with expression in the desired direction were extracted. Our results disclosed some DE circRNAs with potential oncogenic (circ_0014879) or tumor suppressive (circ_0001666 and circ_0000977) effects. Finally, PPI network suggests pivotal roles for DOCK2 and PTPRC dysregulation in progression of CRC, possibly by facilitating of tumor escape from immune surveillance.
Conclusion: Current study proposes a novel regulatory network consisting of DE circRNAs, miRNAs and mRNAs in CRC development that in turn highlights the roles of DE circRNAs at the upstream of oncotranscriptomic cascade in CRC development, suggesting their potentiality to be utilized as both prognostic and therapeutic biomarker.
- colorectal cancer
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018; 68(6): 394-424.
Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, et al. The landscape of circular RNA in cancer. Cell. 2019; 176(4): 869-881. e813.
Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146(3): 353-358.
Guan Yj, Ma JY, Song W. Identification of circRNA–miRNA–mRNA regulatory network in gastric cancer by analysis of microarray data. Cancer Cell International. 2019; 19(1): 183.
Sun X, Ge X, Xu Z, Chen D. Identification of circRNA-miRNA-mRNA regulatory network in hepatocellular carcinoma by integrated analysis. Journal of Gastroenterology and Hepatology.2019
Xu H, Wang C, Song H, Xu Y, Ji G. RNA-Seq profiling of circular RNAs in human colorectal Cancer liver metastasis and the potential biomarkers. Molecular cancer. 2019; 18(1): 8.
Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M. CircInteractome: a web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA biology. 2016; 13(1): 34-42.
Chou CH, Chang NW, Shrestha S, Hsu SD, Lin YL, Lee WH, et al. miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic acids research. 2015; 44(D1): D239-D247.
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell. 2003; 115(7): 787-798.
Vejnar C E, Blum M, Zdobnov EM. miRmap web: comprehensive microRNA target prediction online. Nucleic acids research. 2013; 41(W1): W165-W168.
Xia S, Feng J, Chen K, Ma Y, Gong J, Cai F, et al. CSCD: a database for cancer-specific circular RNAs. Nucleic acids research. 2017; 46(D1): D925-D929.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic acids research. 2017; 45(W1): W98-W102.
Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, et al. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic acids research. 2007; 35(suppl_2): W169-W175.
Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucleic acids research: gkw937. 2016.
Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic acids research. 2016; 44(W1): W90-W97.
Gao J, Lindsay J, Watt S, Bahceci I, Lukasse P, Abeshouse A, et al. The cBioPortal for cancer genomics and its application in precision oncology, AACR. 2016.
Chen S, Zhao Y. Circular RNAs: Characteristics, function, and role in human cancer. Histology and histopathology. 2018; 33(9): 887-893.
Guo JN, Li J, Zhu CL, Feng WT, Shao JX, Wan L, et al. Comprehensive profile of differentially expressed circular RNAs reveals that hsa_circ_0000069 is upregulated and promotes cell proliferation, migration, and invasion in colorectal cancer. OncoTargets and therapy. 2016; 9: 7451.
Wu Y, He C, Hu S, Hu Z, Li Y, Xing X, Du X. Downregulation of ARG2 inhibits growth of colorectal cancer cells and increases expression of the CD3ζ chain in co-cultured T-cells. international journal of clinical and experimental medicine. 2019; 12(6): 6946-6957.
Akino K, Toyota M, Suzuki H, Mita H, Sasaki Y, Ohe-Toyota M, et al. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer. Gastroenterology. 2005; 129(1): 156-169.
Zadka Ł, Kulus MJ, Kurnol K, Piotrowska A, Glatzel-Plucińska N, Jurek T, et al. The expression of IL10RA in colorectal cancer and its correlation with the proliferation index and the clinical stage of the disease. Cytokine. 2018; 110: 116-125.
Ohashi T, Idogawa M, Sasaki Y, Suzuki H, T. Tokino. AKR1B10, a transcriptional target of p53, is downregulated in colorectal cancers associated with poor prognosis. Molecular Cancer Research. 2013; 11(12): 1554-1563.
D'Arrigo A, Belluco C, Ambrosi A, Digito M, Esposito G, Bertola A, et al. Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma. International journal of cancer.2005; 115(2): 256-262.
Ashktorab H, Daremipouran M, Goel A, Varma S, Leavitt R, Sun X, Brim H. DNA methylome profiling identifies novel methylated genes in African American patients with colorectal neoplasia. Epigenetics. 2014; 9(4): 503-512.
Cusick JK, Mustian A, Goldberg K, Reyland M. RELT induces cellular death in HEK 293 epithelial cells. Cellular immunology. 2010; 261(1): 1-8.
Moua P, Checketts M, Xu LG, Shu HB, Reyland ME, Cusick JK. RELT family members activate p38 and induce apoptosis by a mechanism distinct from TNFR1. Biochemical and biophysical research communications. 2017; 491(1): 25-32.
Lines JL, Sempere LF, Broughton T, Wang L, Noelle R. VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer immunology research. 2014; 2(6): 510-517.
Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O'Connell S, et al. VISTA is an immune checkpoint molecule for human T cells. Cancer research. 2014; 74(7): 1924-1932.
Xie S, Huang J, Qiao Q, Zang W, Hong S, Tan H, et al. Expression of the inhibitory B7 family molecule VISTA in human colorectal carcinoma tumors. Cancer Immunology, Immunotherapy. 2018; 67(11): 1685-1694.
Chen L, Zhu YY, Zhang XJ, Wang G, Li XY, He S, et al. TSPAN1 protein expression: a significant prognostic indicator for patients with colorectal adenocarcinoma. World Journal of Gastroenterology: WJG. 2009; 15(18): 2270.
Chen L, Yuan D, Zhao R, Li H, Zhu J. Suppression of TSPAN1 by RNA interference inhibits proliferation and invasion of colon cancer cells in vitro. Tumori Journal. 2010; 96(5): 744-750.
Chen Y, Meng F, Wang B, He L, Liu Y, Liu Z. Dock2 in the development of inflammation and cancer. European journal of immunology. 2018; 48(6): 915-922.
Yu J, Wu WK, Li X, He J, Li XX, Ng SS, et al. Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer. Gut. 2015; 64(4): 636-645.
Liu J, Li H, Sun L, Wang Z, Xing C, Yuan Y. Aberrantly methylated-differentially expressed genes and pathways in colorectal cancer. Cancer Cell International. 2017; 17(1): 75.
Bankaitis-Davis DM, Siconolfi L, Storm K, Wassmann K. Gene Expression Profiling for Identification, Monitoring and Treatment of Prostate Cancer, Google Patents.2010
Kafetzopoulou LE, Boocock DJ, Dhondalay GKR, Powe DG, Ball GR. Biomarker identification in breast cancer: beta-adrenergic receptor signaling and pathways to therapeutic response. Computational and structural biotechnology journal. 2013; 6(7): e201303003.
Guo S, Fesler A, Wang H, Ju J. microRNA based prognostic biomarkers in pancreatic Cancer.Biomarker research. 2018; 6(1): 18.
Hou S, Tan J, Yang B, He L, Zhu Y. Effect of alkylglycerone phosphate synthase on the expression profile of circRNAs in the human thyroid cancer cell line FRO. Oncology letters. 2018; 15(5): 7889-7899.
Su H, Lin F, Deng X, Shen L, Fang Y, Fei Z, et al. Profiling and bioinformatics analyses reveal differential circular RNA expression in radioresistant esophageal cancer cells. Journal of translational medicine. 2016; 14(1): 225.
Qiu L, Wang T, Ge Q, Xu H, Wu Y, Tang Q, Chen K. Circular RNA Signature in Hepatocellular Carcinoma. Journal of Cancer. 2019; 10(15): 3361.
Ou M, Lin H, Gong W, Liu F, Chen P, Zhang Y, et al. Comprehensive analysis of circRNA expression patterns in small hepatocellular carcinoma by integrating circRNA and gene expression data. Int J Clin Exp Med. 2017; 10(2): 2858-2865.
Li QH, Liu Y, Chen S, Zong ZH, Du YP, Sheng XJ, Zhao Y. circ-CSPP1 promotes proliferation, invasion and migration of ovarian cancer cells by acting as a miR-1236-3p sponge. Biomedicine & Pharmacotherapy. 2019; 114: 108832.
Reid JF, Sokolova V, Zoni E, Lampis A, Pizzamiglio S, Bertan C, et al. miRNA profiling in colorectal cancer highlights miR-1 involvement in MET-dependent proliferation. Molecular Cancer Research. 2012; 10(4): 504-515.
Afanasyeva EA, Mestdagh P, Kumps C, Vandesompele J, Ehemann V, Theissen J, et al. MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival. Cell death and differentiation. 2011; 18(6): 974.
Zhang Z, Yin J, Yang J, Shen W, Zhang C, Mou W, et al. miR-885-5p suppresses hepatocellular carcinoma metastasis and inhibits Wnt/β-catenin signaling pathway. Oncotarget. 2016; 7(46): 75038.
Chen L, Li Y, Fu Y, Peng J, Mo MH, Stamatakos M, et al. Stojadinovic, M. Grinkemeyer. Role of deregulated microRNAs in breast cancer progression using FFPE tissue. PloS one. 2013; 8(1): e54213.
Jin S, Dai Y, Li C, Fang X, Han H, Wang D. MicroRNA-544 inhibits glioma proliferation, invasion and migration but induces cell apoptosis by targeting PARK7. American journal of translational research. 2016; 8(4): 1826.
Xiong DD, Dang YW, Lin P, Wen DY, He RQ, Luo DZ, et al. A circRNA–miRNA–mRNA network identification for exploring underlying pathogenesis and therapy strategy of hepatocellular carcinoma. Journal of translational medicine. 2018; 16(1): 220.
Hou BH, Jian ZX, Cui P, Li SJ, Tian RQ, Ou JR. miR-216a may inhibit pancreatic tumor growth by targeting JAK2. FEBS letters. 2015; 589(17): 2224-2232.
Anauate AC, Leal MF, Wisnieski F, Santos LC, Gigek CO, Chen ES, et al. Analysis of 8q24. 21 miRNA cluster expression and copy number variation in gastric cancer. Future medicinal chemistry. 2019; 11(09): 947-958.
Huppi K, Volfovsky N, Runfola T, Jones TL, Mackiewicz M, Martin SE, et al. The identification of microRNAs in a genomically unstable region of human chromosome 8q24. Molecular Cancer Research. 2008; 6(2): 212-221.
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