A Computational Approach to Identify Novel Potential Precursor miRNAs and their Targets from Hepatocellular Carcinoma Cells

Author(s): Chitra Jeyaram, Manuel Philip, Rajadurai Chinnasamy Perumal, Jubina Benny, Jayasankar Madusoodhanan Jayakumari, Maniramakrishnan Santhana Ramasamy*.

Journal Name: Current Bioinformatics

Volume 14 , Issue 1 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Recent advances in next-generation sequencing technology allow highthroughput RNA-Sequencing to be widely applied in studying coding and non-coding RNA profiling in cells. RNA-Seq data usually contains functional transcriptomic and other small and larger non-coding (nc) RNA sequences.

Objective: MicroRNAs (miRNAs), a small nc-RNA act as epigenetic markers and the expression of their target genes and pathways that regulate Hepatocellular Carcinoma (HCC), a primary malignancy of the liver. The unreported potential novel miRNAs targeting HCC pathways can be identified from the sequenced data.

Methods: In this study, we performed a computational identification of novel putative miRNAs and their targets from publicly available high-throughput sequencing Fastq data of human HCC cells HepG2, NorHep and SKHep1, retrieved from NCBI-SRA.

Results: Totally, 572 unique known precursor miRNAs and 1062 unique novel miRNAs were identified from HepG2, Nor and SKHep1 HCC cell lines. Interestingly, 140 novel miRNAs were predicted to be extensively involved in targeting genes of HCC related pathways such as apoptosis, cell signaling, cell division, cell-cycle arrest, GPCR, MAPK cascade, TOR signaling, TNFSF11 signaling and liver development.

Conclusion: The predicted novel miRNAs reported in the paper might have a vital role in regulating the molecular mechanism of HCC and thus, further studies on these miRNAs will provide significant clues for researchers into the complex biological process of liver cancer.

Keywords: Hepatocellular Carcinoma, microRNA, high-throughput sequencing, targets, pathways, computational.

Shu-Ting W, Cai L, Lei L. miRNA Microarray Technology in miRNA Profiling. Curr Bioinform 2009; 4(2): 141-8.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136(2): 215-33.
Fabian MR, Sonenberg N. The mechanics of miRNAmediated gene silencing: a look under the hood of miRISC. Nat Struct Mol Biol 2012; 19(6): 586-93.
Saj A, Lai EC. Control of microRNA biogenesis and transcription by cell signaling pathways. Curr Opin Genet Dev 2011; 21(4): 504-10.
Kasinski AL, Slack FJ. Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer 2011; 11(12): 849-64.
Stahlhut C, Slack FJ. MicroRNAs and the cancer phenotype: profiling, signatures and clinical implications. Genome Med 2013; 5(12): 111.
Negrini M, Ferracin M, Sabbioni S, Croce CM. MicroRNAs in human cancer: from research to therapy. J Cell Sci 2007; 120: 1833-40.
Dolganiuc A, Petrasek J, Kodys K, et al. MicroRNA expression profile in Lieber-DeCarli diet-induced alcoholic and methionine choline deficient diet-induced nonalcoholic steatohepatitis models in mice. Alcohol Clin Exp Res 2009; 33: 1704-10.
Banaudha KK, Verma M. The role of microRNAs in the management of liver cancer. Methods Mol Biol 2012; 863: 241-51.
Gramantieri L, Fornari F, Callegari E, et al. MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med 2008; 12: 2189-204.
Murakami Y, Yasuda T, Saigo K, et al. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 2006; 25: 2537-45.
Ladeiro Y, Couchy G, Balabaud C, et al. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology 2008; 47: 1955-63.
Guichard C, Amaddeo G, Imbeaud S, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012; 44: 694-8.
Cleary SP, Jeck WR, Zhao X, et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology 2013; 58: 1693-702.
Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology 2011; 140: 1410-26.
Faivre S, Bouattour M, Raymond E. Novel molecular therapies in hepatocellular carcinoma. Liver Int 2011; 31(Suppl. 1): 151-60.
Lu M, Kong X, Wang H, et al. A novel microRNAs expression signature for hepatocellular carcinoma diagnosis and prognosis. Oncotarget 2017; 8(5): 8775-84.
Mohamed AA, Ali-Eldin ZA, Elbedewy TA, et al. MicroRNAs and clinical implications in hepatocellular carcinoma. World J Hepatol 2017; 9(23): 1001-7.
Ding Y, Yan JL, Fang AN, et al. Circulating miRNAs as novel diagnostic biomarkers in hepatocellular carcinoma detection: a meta-analysis based on 24 articles. Oncotarget 2017; 8(39): 66402-13.
Leggett RM, Ramirez-Gonzalez RH, Clavijo BJ, Waite D, Davey RP. Sequencing quality assessment tools to enable data-driven informatics for high throughput genomics. Front Genet 2013; 4: 288.
Chen C, Khaleel SS, Huang H, Wu CH. Software for pre-processing Illumina next-generation sequencing short read sequences. Source Code Biol Med 2014; 9: 8.
Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods 2012; 9(4): 357-9.
Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase:microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006; 34(Database issue): D140-4.
Li G, Hui Z, Yang Z, et al. In-Depth Exploration of miRNA: A New Approach to Study miRNA at the miRNA/isomiR Levels. Curr Bioinform 2014; 9(5): 522-30.
Wang L, Liu H, Li D, Chen H. Identification and characterization of maize microRNAs involved in the very early stage of seed germination. BMC Genomics 2011; 12: 154.
Leyi W, Yong H, Yanyun Q, et al. Computational analysis of miRNA target identification. Curr Bioinform 2012; 7(4): 512-25.
John B, Enright AJ, Aravin A, et al. Human microRNA targets. PLoS Biol 2004; 2(11): e363.
Harris MA, Clark J, Ireland A, et al. The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res 2004; 32(Database issue): D258-61.
Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 2017; 45: D353-61.
Dennis G Jr, Sherman BT, Hosack DA, et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 2003; 4(5): 3.
Boutet E, Lieberherr D, Tognolli M, et al. UniProtKB/Swiss-Prot, the Manually Annotated Section of the UniProt KnowledgeBase: How to Use the Entry View. Methods Mol Biol 2016; 1374: 23-54.
Kuhlwilm M, Davierwala A, Paabo S. Identification of putative target genes of the transcription factor RUNX2. PLoS One 2013; 8(12): e83218.
Zhang J, Wang Y, Zhen P, et al. Genome-wide analysis of miRNA signature differentially expressed in doxorubicin-resistant and parental human hepatocellular carcinoma cell lines. PLoS One 2013; 8(1): e54111.
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. eLife 2015; 4.
Sugeno H, Takebayashi Y, Higashimoto M, et al. Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) in human hepatocellular carcinoma. Anticancer Res 2004; 24(2C): 1045-8.
Schee K, Lorenz S, Worren MM, et al. Deep Sequencing the MicroRNA Transcriptome in Colorectal Cancer. PLoS One 2013; 8(6): e66165.
Liu H, Liu Y, Liu W, Zhang W, Xu J. EZH2-mediated loss of miR-622 determines CXCR4 activation in hepatocellular carcinoma. Nat Commun 2015; 6: 8494.
Arretxe E, Armengol S, Mula S, et al. Profiling of promoter occupancy by the SND1 transcriptional coactivator identifies downstream glycerolipid metabolic genes involved in TNFα response in human hepatoma cells. Nucleic Acids Res 2015; 43(22): 10673-88.
Hou DL, Chen L, Liu B, Song LN, Fang T. Identification of common gene networks responsive to radiotherapy in human cancer cells. Cancer Gene Ther 2014; 21(12): 542-8.
Wang K. Molecular mechanisms of hepatic apoptosis. Cell Death Dis 2014; 5: e996.
Shan CM, Li J. Study of apoptosis in human liver cancers. World J Gastroenterol 2002; 8(2): 247-52.
Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer 2007; 7(2): 79-94.
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007; 26(22): 3279-90.
Bisteau X, Caldez MJ, Kaldis P. The Complex Relationship between Liver Cancer and the Cell Cycle: A Story of Multiple Regulations. Cancers (Basel) 2014; 6(1): 79-111.
Haagenson KK, Wu GS. Mitogen activated protein kinase phosphatases and cancer. Cancer Biol Ther 2010; 9(5): 337-40.
Beauchamp EM, Platanias LC. The evolution of the TOR pathway and its role in cancer. Oncogene 2013; 32(34): 3923-32.
Bueno MJ, Malumbres M. MicroRNAs and the cell cycle. Biochim Biophys Acta 2011; 1812(5): 592-6.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [24 - 32]
Pages: 9
DOI: 10.2174/1574893613666180413150351
Price: $58

Article Metrics

PDF: 36