Abstract
MicroRNAs could be promising biomarkers for various diseases, and small RNA drugs have already been FDA approved for clinical use. This area of research is rapidly expanding and has significant potential for the future. Fennel (Anethum foeniculum) is a highly esteemed spice plant with economic and medicinal benefits, making it an invaluable asset in the pharmaceutical industry. To characterize the fennel miRNAs and their Arabidopsis thaliana and Homo sapience targets with functional enrichment analysis and human disease association. A homology-based computational approach characterized the MiRnome of the Anethum foeniculum genome and assessed its impact on Arabidopsis thaliana and Homo sapience transcriptomes. In addition, functional enrichment analysis was evaluated for both species’ targets. Moreover, PPI network analysis, hub gene identification, and MD simulation analysis of the top hub node with fennel miRNA were incorporated. We have identified 100 miRNAs of fennel and their target genes, which include 2536 genes in Homo sapiens and 1314 genes in Arabidopsis thaliana. Functional enrichment analysis reveals 56 Arabidopsis thaliana targets of fennel miRNAs showed involvement in metabolic pathways. Highly enriched human KEGG pathways were associated with several diseases, especially cancer. The protein–protein interaction network of human targets determined the top ten nodes; from them, seven hub nodes, namely MAPK1, PIK3R1, STAT3, EGFR, KRAS, CDC42, and SMAD4, have shown their involvement in the pancreatic cancer pathway. Based on the Blast algorithm, 21 fennel miRNAs are homologs to 16 human miRNAs were predicted; from them, the CSPP1 target was a common target for afo-miR11117a-3p and has-miR-6880-5p homologs miRNAs. Our results are the first to report the 100 fennel miRNAs, and predictions for their endogenous and human target genes provide a basis for further understanding of Anethum foeniculum miRNAs and the biological processes and diseases with which they are associated.
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Data Availability
The data used and analyzed during the current study are available from the corresponding author upon reasonable request.
Abbreviations
- A. foeniculum :
-
Anethum foeniculum
- miRNA:
-
microRNA
- EP300 :
-
E1A-binding protein p300
- MAPK1 :
-
MAPK1 mitogen-activated protein kinase 1
- PIK3R1 :
-
Phosphoinositide-3-kinase regulatory subunit 1
- STAT3 :
-
Signal transducer and activator of transcription 3
- RAC1 :
-
Rac Family Small GTPase 1
- EGFR :
-
Epidermal Growth Factor Receptor
- KRAS :
-
KRAS Proto-Oncogene
- CDC42 :
-
Cell Division Cycle 42
- SMAD4 :
-
SMAD Family Member 4
- PXN :
-
Paxillin
- CSPP1 :
-
Centrosome and Spindle Pole-Associated Protein 1
- PC:
-
Pancreatic cancer
- LDLRAP1 :
-
Low-Density Lipoprotein Receptor Adaptor Protein 1
- H. sapiens :
-
Homo sapiens
- A. thaliana :
-
Arabidopsis thaliana
- MFE:
-
Minimal Folding Free Energy
- MFEI:
-
Minimal Folding Free Energy Index
- AMFE:
-
Adjusted Minimal Folding Free Energy
- MDS:
-
Molecular dynamics simulation
References
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215(3):403–410
Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Tuschl T (2003) A uniform system for microRNA annotation. RNA 9(3):277–279
Antczak M, Popenda M, Zok T, Sarzynska J, Ratajczak T, Tomczyk K, Szachniuk M (2016) New functionality of RNAComposer: an application to shape the axis of miR160 precursor structure. Acta Biochim Pol 63(4):737–744
Avalle L, Camporeale A, Camperi A, Poli V (2017) STAT3 in cancer: a double edged sword. Cytokine 98:42–50. https://doi.org/10.1016/j.cyto.2017.03.018
Avsar B, Zhao Y, Li W, Lukiw WJ (2020) Atropa belladonna expresses a microRNA (aba-miRNA-9497) highly homologous to Homo sapiens miRNA-378 (hsa-miRNA378); both miRNAs target the 3′ -untranslated region (3′ -UTR) of the mRNA encoding the neurologically relevant, zinc-finger transcription factor. Cell Mol Neurobiol 40:179–188. https://doi.org/10.1007/s10571-019-00729-w
Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, Hruban RH (2009) SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 15(14):4674–4679
Bu D, Luo H, Huo P, Wang Z, Zhang S, He Z, Kong L (2021) KOBAS-i: intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis. Nucleic Acids Res 49(W1):W317–W325
Catassi C, Bai JC, Bonaz B, Bouma G, Calabro A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, V’ecsei A, Volta U, Zevallos V, Sapone A, Fasano A (2013) Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 5:3839–3853. https://doi.org/10.3390/nu5103839
Chandradoss SD, Schirle NT, Szczepaniak M, Macrae IJ, Joo C (2015) A dynamic search process underlies MicroRNA targeting. Cell 162:96–107. https://doi.org/10.1016/j.cell.2015.06.032
Cheung LW, Yu S, Zhang D, Li J, Ng PK, Panupinthu N, Mills GB (2014) Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer Cell 26(4):479–494
Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY (2014) cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 8(4):1–7
Chin AR, Fong MY, Somlo G, Wu J, Swiderski P, Wu X, Wang SE (2016) Cross-kingdom inhibition of breast cancer growth by plant miR159. Cell Res 26:217–228. https://doi.org/10.1038/cr.2016.13
Dai X, Zhuang Z, Zhao PX (2018) psRNATarget: a plant small RNA target analysis server (2017 release). Nucleic Acids Res 46(W1):W49–W54
Diao WR, Hu QP, Zhang H, Xu JG (2014) Chemical composition, antibacterial activity and mechanism of action of essential oil from seeds of Fennel (Foeniculum vulgare Mill.). Food Control 35(1):109–116
Farré G, Blancquaert D, Capell T, Van Der Straeten D, Christou P, Zhu C (2014) Engineering complex metabolic pathways in plants. Annu Rev Plant Biol 65:187–223
Fathi N, Rashidi G, Khodadadi A, Shahi S, Sharifi S (2018) STAT3 and apoptosis challenges in cancer. Int J Biol Macromol 117:993–1001. https://doi.org/10.1016/j.ijbiomac.2018.05.121
Frazier TP, Xie F, Freistaedter A, Burklew CE, Zhang B (2010) Identification and characterization of microRNAs and their target genes in tobacco (Nicotiana tabacum). Planta 232:1289–1308
Friedman RC, Farh KK-H, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105. https://doi.org/10.1101/gr.082701.108
Fritz G, Brachetti C, Bahlmann F, Schmidt M, Kaina B (2002) Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters. Br J Cancer 87(6):635–644
Gao QQ, Putzbach WE, Murmann AE, Chen S, Sarshad AA, Peter JM, Bartom ET, Hafner M, Peter ME (2018) 6mer seed toxicity in tumor suppressive microRNAs. Nat Commun. https://doi.org/10.1038/s41467-018-06526-1
Gore J, Imasuen-Williams IE, Conteh AM, Craven KE, Cheng M, Korc M (2016) Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model. Cancer Lett 379(1):143–153
Graves P, Zeng Y (2012) Biogenesis of mammalian microRNAs: a global view. Genomics Proteomics Bioinform 10(5):239–245
Griffiths-Jones S, Grocock RJ, Van Dongen S, Bateman A, Enright AJ (2006) miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34(Suppl 1):D140–D144
Gu W, Xu Y, Xie X, Wang T, Ko JH, Zhou T (2014) The role of RNA structure at 5′ untranslated region in microRNA-mediated gene regulation. RNA 20:1369–1375. https://doi.org/10.1261/rna.044792.114
Hofacker IL (2003) Vienna RNA secondary structure server. Nucleic Acids Res 31(13):3429–3431
Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12:99–110. https://doi.org/10.1038/nrg2936
Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28(1):27–30
Karakus YY, Yildirim B, Acemi A (2021) Characterization of polyphenol oxidase from Fennel (Foeniculum vulgare Mill.) seeds as a promising source. Int J Biol Macromol 170:261–271
Klaiber U, Leonhardt CS, Strobel O, Tjaden C, Hackert T, Neoptolemos JP (2018) Neoadjuvant and adjuvant chemotherapy in pancreatic cancer. Langenbecks Arch Surg 403:917–932
Klein M, Chandradoss SD, Depken M, Joo C (2017) Why Argonaute is needed to make microRNA target search fast and reliable. Semin Cell Dev Biol 65:20–28. https://doi.org/10.1016/j.semcdb.2016.05.017
Klum SM, Chandradoss SD, Schirle NT, Joo C, Macrae IJ (2018) Helix-7 in Argonaute2 shapes the microRNA seed region for rapid target recognition. EMBO J 37:75–88. https://doi.org/10.15252/embj.201796474
Lam JKW, Chow MYT, Zhang Y, Leung SWS (2015) siRNA versus miRNA as therapeutics for gene silencing, mol. Ther Nucleic Acids 4:e252. https://doi.org/10.1038/mtna.2015.23
Land H, Humble MS (2018) YASARA: a tool to obtain structural guidance in biocatalytic investigations. Protein Eng 43–67
Lee I, Ajay SS, Yook JI, Kim HS, Hong SH, Kim NH, Athey BD (2009) New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites. Genome Res 19(7):1175–1183
Li M, Chen T, He JJ, Wu JH, Luo JY, Ye RS, Xie MY, Zhang HJ, Zeng B, Liu J, Xi QY, Jiang QY, Sun JJ, Zhang YL (2019) Plant MIR167e-5p inhibits enterocyte proliferation by targeting β-catenin. Cells 8:1–14. https://doi.org/10.3390/cells8111385
Liang H, Zhang S, Fu Z, Wang Y, Wang N, Liu Y, Zhang CY (2015) Effective detection and quantification of dietetically absorbed plant microRNAs in human plasma. J Nutr Biochem 26(5):505–512
Liou GY, Döppler H, DelGiorno KE, Zhang L, Leitges M, Crawford HC, Storz P (2016) Mutant KRas-induced mitochondrial oxidative stress in acinar cells upregulates EGFR signaling to drive formation of pancreatic precancerous lesions. Cell Rep 14(10):2325–2336
Liu C, Rennie WA, Carmack CS, Kanoria S, Cheng J, Lu J, Ding Y (2014) Effects of genetic variations on microRNA: target interactions. Nucleic Acids Res 42:9543–9552. https://doi.org/10.1093/nar/gku675
Ma J, Xue Y, Liu W, Yue C, Bi F, Xu J, Chen Y (2013) Role of activated rac1/cdc42 in mediating endothelial cell proliferation and tumor angiogenesis in breast cancer. PLoS ONE 8(6):e66275
Maere S, Heymans K, Kuiper M (2005) BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21(16):3448–3449
Minutolo A, Potesta M, Gismondi A, Pirro S, Cirilli M, Gattabria F, Galgani A, Sessa L, Mattei M, Canini A, Muleo R, Colizzi V, Montesano C (2018) Olea europaea small RNA with functional homology to human miR34a in cross-kingdom interaction of anti-tumoral response. Sci Rep 8:1–14. https://doi.org/10.1038/s41598-018-30718-w
Motwani H, Gadhavi H, Mangukia N, Dixit N, Rawal RM, Patel SK, Solanki HA (2023) Deciphering the role of Andrographis paniculata micro-RNAs in regulation of cancer. Human Gene 36:201162
Nikolic A, Kojic S, Knezevic S, Krivokapic Z, Ristanovic M, Radojkovic D (2011) Structural and functional analysis of SMAD4 gene promoter in malignant pancreatic and colorectal tissues: detection of two novel polymorphic nucleotide repeats. Cancer Epidemiol 35(3):265–271
Pang W, Yao W, Dai X, Zhang A, Hou L, Wang L, Wang Y, Huang X, Meng X, Li L (2021) Pancreatic cancer-derived exosomal microrna-19a induces β-cell dysfunction by targeting adcy1 and epac2. Int J Biol Sci 17:3622–3633. https://doi.org/10.7150/ijbs.56271
Pasquinelli AE (2012) MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 13(4):271–282
Patel M, Mangukia N, Jha N, Gadhavi H, Shah K, Patel S, Rawal R (2019) Computational identification of miRNA and their cross kingdom targets from expressed sequence tags of Ocimum basilicum. Mol Biol Rep 46:2979–2995
Pavela R, Žabka M, Bednář J, Tříska J, Vrchotová N (2016) New knowledge for yield, composition and insecticidal activity of essential oils obtained from the aerial parts or seeds of Fennel (Foeniculum vulgare Mill.). Ind Crops Prod 83:275–282
Perge P, Nagy Z, Decmann Á, Igaz I, Igaz P (2017) Potential relevance of microRNAs in inter-species epigenetic communication, and implications for disease pathogenesis. RNA Biol 14(4):391–401
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612
Rakhmetullina A, Pyrkova A, Aisina D, Ivashchenko A (2020) In silico prediction of human genes as potential targets for rice miRNAs. Comput Biol Chem 87:107305. https://doi.org/10.1016/j.compbiolchem.2020.107305
Romo DS, Alferez BP, Garcia JHG (2022) Effect in human gene regulation of food-derived plant miRNAs. In: Medicinal Plants. IntechOpen
Samad AFA, Kamaroddin MF, Sajad M (2020) Cross-kingdom regulation by plant microRNAs provides novel insight into gene regulation. Adv Nutr. https://doi.org/10.1093/advances/nmaa095
Schoch CL, Ciufo S, Domrachev M, Hotton CL, Kannan S, Khovanskaya R, Karsch-Mizrachi I (2020) NCBI Taxonomy: a comprehensive update on curation, resources and tools. Database
Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA: A Cancer Journal for Clinicians 68(1):7–30
Sleightholm RL, Neilsen BK, Li J, Steele MM, Singh RK, Hollingsworth MA, Oupicky D (2017) Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy. Pharmacol Ther 179:158–170
Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T (2011) Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27(3):431–432
Stephen BJ, Pareek N, Saeed M, Kausar MA, Rahman S, Datta M (2020) Xeno-miRNA in maternal-infant immune crosstalk: An aid to disease alleviation. Front Immunol 11:404
Stoll V, Calleja V, Vassaux G, Downward J, Lemoine NR (2005) Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer. Gut 54(1):109–116
Sun Y, Zhang M, Bhandari B, Bai B (2021) Fennel essential oil loaded porous starch-based microencapsulation as an efficient delivery system for the quality improvement of ground pork. Int J Biol Macromol 172:464–474
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, von Mering C (2023) The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res 51(D1):D638–D646
Tamura K, Stecher G, Kumar S (2021) MEGA11: molecular evolutionary genetics analysis version 11. Mol Biol Evol 38(7):3022–3027. https://doi.org/10.1093/molbev/msab120
Trivedi TS, Mangukia N, Bhavsar M, Mankad AU, Rawal RM, Patel SK (2023a) A novel insight of Picrorhiza kurroa miRNAs in human cystic fibrosis: a transcriptome-wide cross-kingdom study. Human Gene 35:201153
Trivedi TS, Patel MP, Nanavaty V et al (2023b) MicroRNAs from Holarrhena pubescens stems: identification by small RNA sequencing and their potential contribution to human gene targets. Funct Integr Genomics 23:149. https://doi.org/10.1007/s10142-023-01078-0
Tuz K, Bachmann-Gagescu R, O’Day DR, Hua K, Isabella CR, Phelps IG, Ferland RJ (2014) Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Am J Hum Genet 94(1):62–72
Van Emburgh BO, Arena S, Siravegna G, Lazzari L, Crisafulli G, Corti G, Bardelli A (2016) Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer. Nat Commun 7(1):13665
Wang LH, Kim SH, Lee JH, Choi YL, Kim YC, Park TS, Shin YK (2007) Inactivation of SMAD4 tumor suppressor gene during gastric carcinoma progression. Clin Cancer Res 13(1):102–110
Waters AM, Der CJ (2018) KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med 8(9):a031435
Yang D, Zhang Y, Cheng Y, Hong L, Wang C, Wei Z, Yan R (2017) High expression of cell division cycle 42 promotes pancreatic cancer growth and predicts poor outcome of pancreatic cancer patients. Dig Dis Sci 62:958–967
Zhang B, Pan X, Stellwag EJ (2008) Identification of soybean microRNAs and their targets. Planta 229:161–182
Zhang L, Hou D, Chen X, Li D, Zhu L, Zhang Y, Zhang CY (2012) Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res 22(1):107–126
Zhang ZY, Gao XH, Ma MY, Zhao CL, Zhang YL, Guo SS (2020) CircRNA_101237 promotes NSCLC progression via the miRNA-490-3p/MAPK1 axis. Sci Rep 10(1):1–10
Zhao Y, Cong L, Lukiw WJ (2018) Plant and animal microRNAs (miRNAs) and their potential for inter-kingdom communication. Cell Mol Neurobiol 38:133–140
Zhou Z, Li X, Liu J, Dong L, Chen Q, Liu J, Kong H, Zhang Q, Qi X, Hou D, Zhang L, Zhang G, Liu Y, Zhang Y, Li J, Wang J, Chen X, Wang H, Zhang J, Chen H, Zen K, Zhang CY (2015) Honeysuckle-encoded atypical microRNA2911 directly targets influenza A viruses. Cell Res 25:39–49. https://doi.org/10.1038/cr.2014.130
Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31(13):3406–3415
Acknowledgements
The authors acknowledge GUJCOST, DST, and Government of Gujarat for providing the Super-computing facility and we acknowledge GSBTM, DST, and Government of Gujarat for providing BIN-Node Facility to our department. Author Tithi S. Trivedi would like to acknowledge the ScHeme Of Developing High-quality research (SHODH), Education Department, Government of Gujarat, INDIA, for providing the student support fellowship. Authors Tithi S. Trivedi and Aafrinbanu M. Shaikh acknowledge Mrs. Sukanya P. Raval for resolving the queries and Ms. Simran Rohra for helping as a supportive companion during the analysis. Authors Tithi S. Trivedi acknowledges Dr. Pujan Pandya, Ms. Pooja Prajapati, and Mr. Mayur Chavda for helping in manuscript revision.
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TST: Conceptualization, Software, Methodology, Data Analysis, Writing—original draft, Writing—review & editing. AMS: Software, Data analysis. AUM: Supervision, Funding acquisition. RMR: Visualization, Supervision, Investigation. SKP: Visualization, Supervision, Investigation, Funding acquisition, Writing—review & editing.
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Trivedi, T.S., Shaikh, A.M., Mankad, A.U. et al. Genome-Wide Characterization of Fennel (Anethum foeniculum) MiRNome and Identification of its Potential Targets in Homo sapiens and Arabidopsis thaliana: An Inter and Intra-species Computational Scrutiny. Biochem Genet (2023). https://doi.org/10.1007/s10528-023-10575-7
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DOI: https://doi.org/10.1007/s10528-023-10575-7