{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T09:25:40Z","timestamp":1771579540171,"version":"3.50.1"},"reference-count":65,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,20]],"date-time":"2022-02-20T00:00:00Z","timestamp":1645315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>New selective, efficacious chemotherapy agents are in demand as traditional drugs display side effects and face growing resistance upon continued administration. To this end, bioactive molecules such as peptides are attracting interest. RT2 is a cationic peptide that was used as an antimicrobial but is being repurposed for targeting cancer. In this work, we investigate the mechanism by which this peptide targets Caco-2 human colon cancer cells, one of the most prevalent and metastatic cancers. Combining label-free proteomics with bioinformatics data, our data explore over 1000 proteins to identify 133 proteins that are downregulated and 79 proteins that are upregulated upon treatment with RT2. These changes occur in a dose-dependent manner and suggest the former group are related to anticancer cell proliferation; the latter group is closely related to apoptosis levels. The mRNA levels of several genes (FGF8, PAPSS2, CDK12, LDHA, PRKCSH, CSE1L, STARD13, TLE3, and OGDHL) were quantified using RT-qPCR and were found to be in agreement with proteomic results. Collectively, the global change in Caco-2 cell protein abundance suggests that RT2 triggers multiple mechanisms, including cell proliferation reduction, apoptosis activation, and alteration of cancerous cell metabolism.<\/jats:p>","DOI":"10.3390\/molecules27041426","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:22:19Z","timestamp":1645431739000},"page":"1426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["An Integrated Proteomics and Bioinformatics Analysis of the Anticancer Properties of RT2 Antimicrobial Peptide on Human Colon Cancer (Caco-2) Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Surachai","family":"Maijaroen","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Protein and Proteomics Research Center for Commercial and Industrial Purposes (ProCCI), Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sompong","family":"Klaynongsruang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Protein and Proteomics Research Center for Commercial and Industrial Purposes (ProCCI), Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-8390","authenticated-orcid":false,"given":"Sittiruk","family":"Roytrakul","sequence":"additional","affiliation":[{"name":"Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani 12120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monruedee","family":"Konkchaiyaphum","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Protein and Proteomics Research Center for Commercial and Industrial Purposes (ProCCI), Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lapatrada","family":"Taemaitree","sequence":"additional","affiliation":[{"name":"Department of Integrated Science, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2071-2406","authenticated-orcid":false,"given":"Nisachon","family":"Jangpromma","sequence":"additional","affiliation":[{"name":"Protein and Proteomics Research Center for Commercial and Industrial Purposes (ProCCI), Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Department of Integrated Science, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11282","DOI":"10.1038\/s41598-019-47568-9","article-title":"In silico design and optimization of selective membranolytic anticancer peptides","volume":"9","author":"Gabernet","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5416923","DOI":"10.1155\/2018\/5416923","article-title":"Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment","volume":"2018","author":"Phi","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.3390\/cancers6031769","article-title":"Drug resistance in cancer: An overview","volume":"6","author":"Housman","year":"2014","journal-title":"Cancers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7351976","DOI":"10.1155\/2017\/7351976","article-title":"Improving in vivo efficacy of bioactive molecules: An overview of potentially antitumor phytochemicals and currently available lipid-based delivery systems","volume":"2017","author":"Mouhid","year":"2017","journal-title":"J. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/j.bbamem.2015.02.021","article-title":"Cationic amphipathic peptides KT2 and RT2 are taken up into bacterial cells and kill planktonic and biofilm bacteria","volume":"1848","author":"Anunthawan","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","first-page":"3919","article-title":"The antimicrobial peptides and their potential clinical applications","volume":"11","author":"Lei","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.4014\/jmb.1510.10074","article-title":"RV-23, a melittin-related peptide with cell-selective antibacterial activity and high hemocompatibility","volume":"26","author":"Zhang","year":"2016","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.ejphar.2017.03.054","article-title":"Selective cytotoxicity of the antibacterial peptide ABP-dHC-Cecropin A and its analog towards leukemia cells","volume":"803","author":"Sang","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"173434","DOI":"10.1016\/j.ejphar.2020.173434","article-title":"Inhibitory effects of Bombyx mori antimicrobial peptide cecropins on esophageal cancer cells","volume":"887","author":"Xu","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.2174\/138920312800785076","article-title":"Identification and design of antimicrobial peptides for therapeutic applications","volume":"13","author":"Ahmad","year":"2012","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s10930-016-9662-1","article-title":"Cationic antimicrobial peptides derived from Crocodylus siamensis leukocyte extract, revealing anticancer activity and apoptotic induction on human cervical cancer cells","volume":"35","author":"Theansungnoen","year":"2016","journal-title":"Protein J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13765-019-0488-3","article-title":"Evidence of multi-functional peptide activity: Potential role of KT2 and RT2 for anti-inflammatory, anti-oxidative stress, and anti-apoptosis properties","volume":"63","author":"Payoungkiattikun","year":"2020","journal-title":"Appl. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.etap.2018.07.007","article-title":"KT2 and RT2 modified antimicrobial peptides derived from Crocodylus siamensis Leucrocin I show activity against human colon cancer HCT-116 cells","volume":"62","author":"Maijaroen","year":"2018","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"793","DOI":"10.2217\/epi-2017-0041","article-title":"Overcoming chemoresistance in cancer stem cells with the help of microRNAs in colorectal cancer","volume":"9","author":"Fesler","year":"2017","journal-title":"Epigenomics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3834","DOI":"10.3748\/wjg.v24.i34.3834","article-title":"Drug resistance and new therapies in colorectal cancer","volume":"24","author":"Xu","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"294","DOI":"10.3389\/fmicb.2013.00294","article-title":"From antimicrobial to anticancer peptides. A review","volume":"4","author":"Gaspar","year":"2013","journal-title":"Front. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ejphar.2009.08.043","article-title":"Cationic amphiphilic peptides with cancer-selective toxicity","volume":"625","author":"Schweizer","year":"2009","journal-title":"Eur. J. Pharmacol."},{"key":"ref_18","first-page":"7052456","article-title":"Label-free LC-MS\/MS proteomics analyses reveal proteomic changes accompanying MSTN KO in C2C12 cells","volume":"2019","author":"Wang","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref_19","unstructured":"Badal, S., and Delgoda, R. (2017). Proteins. Pharmacognosy, Academic Press."},{"key":"ref_20","first-page":"923","article-title":"Transmission of apoptosis in human colorectal tumor cells exposed to capecitabine, xeloda, is mediated via Fas","volume":"1","author":"Ciccolini","year":"2002","journal-title":"Mol. Cancer. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1007\/s13273-011-0015-z","article-title":"Induction of doxorubicin-mediated apoptosis via thioredoxin reductase 1 RNAi in human colon cancer cells","volume":"7","author":"Koedrith","year":"2011","journal-title":"Mol. Cell. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/bjc.1998.617","article-title":"5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins","volume":"78","author":"Nita","year":"1998","journal-title":"Br. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.3892\/ol.2015.2996","article-title":"Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer","volume":"9","author":"Tan","year":"2015","journal-title":"Oncol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"935","DOI":"10.18632\/oncotarget.2822","article-title":"FGF8 promotes colorectal cancer growth and metastasis by activating YAP1","volume":"6","author":"Liu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/sj.onc.1202392","article-title":"Increased expression of fibroblast growth factor 8 in human breast cancer","volume":"18","author":"Marsh","year":"1999","journal-title":"Oncogene"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nrc2780","article-title":"Fibroblast growth factor signalling: From development to cancer","volume":"10","author":"Turner","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.cytogfr.2007.04.010","article-title":"Role of fibroblast growth factor 8 in growth and progression of hormonal cancer","volume":"18","author":"Mattila","year":"2007","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S1357-2725(98)00155-1","article-title":"Molecular cloning of a novel human PAPS synthetase which is differentially expressed in metastatic and non-metastatic colon carcinoma cells","volume":"31","author":"Franzon","year":"1999","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41418-018-0147-y","article-title":"Enhanced PAPSS2\/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis","volume":"26","author":"Zhang","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/cdd.2015.107","article-title":"Heparan sulfation is essential for the prevention of cellular senescence","volume":"23","author":"Jung","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.7150\/ijms.34541","article-title":"Expression pattern of CDK12 protein in gastric cancer and its positive correlation with CD8(+) cell density and CCL12 expression","volume":"16","author":"Ji","year":"2019","journal-title":"Int. J. Med. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13008-017-0033-x","article-title":"The emerging roles of CDK12 in tumorigenesis","volume":"12","author":"Kohoutek","year":"2017","journal-title":"Cell Div."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"zcaa003","DOI":"10.1093\/narcan\/zcaa003","article-title":"CDK12: Cellular functions and therapeutic potential of versatile player in cancer","volume":"2","author":"Pilarova","year":"2020","journal-title":"NAR Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6124","DOI":"10.1002\/cam4.1820","article-title":"Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy","volume":"7","author":"Feng","year":"2018","journal-title":"Cancer Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8093","DOI":"10.1007\/s13277-015-3540-x","article-title":"Inhibition of LDHA suppresses tumor progression in prostate cancer","volume":"36","author":"Xian","year":"2015","journal-title":"Tumour Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1038\/emm.2013.85","article-title":"Cancer cell metabolism: Implications for therapeutic targets","volume":"45","author":"Jang","year":"2013","journal-title":"Exp. Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/978-1-4020-9545-0_15","article-title":"Colorectal cancer: Lactate dehydrogenase (LDH) activity as a prognostic marker","volume":"4","author":"Koukourakis","year":"2009","journal-title":"Colorectal Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Urba\u0144ska, K., and Orzechowski, A. (2019). Unappreciated role of LDHA and LDHB to control apoptosis and autophagy in tumor cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092085"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10394","DOI":"10.1038\/s41598-019-46701-y","article-title":"Knockout of glucosidase II beta subunit inhibits growth and metastatic potential of lung cancer cells by inhibiting receptor tyrosine kinase activities","volume":"9","author":"Khaodee","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"31764","DOI":"10.1038\/srep31764","article-title":"Glucosidase II \u03b2-subunit, a novel substrate for caspase-3-like activity in rice, plays as a molecular switch between autophagy and programmed cell death","volume":"6","author":"Cui","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1038\/s41467-019-11019-w","article-title":"PRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway","volume":"10","author":"Shin","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1016\/j.ajpath.2016.06.016","article-title":"Knockdown of CSE1L gene in colorectal cancer reduces tumorigenesis in vitro","volume":"186","author":"Pimiento","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.7314\/APJCP.2013.14.2.1017","article-title":"Suppression of cellular apoptosis susceptibility (CSE1L) inhibits proliferation and induces apoptosis in colorectal cancer cells","volume":"14","author":"Zhu","year":"2013","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00005-015-0359-5","article-title":"The role of cathelicidin LL-37 in cancer development","volume":"64","author":"Piktel","year":"2016","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.etap.2013.06.009","article-title":"Melittin: A lytic peptide with anticancer properties","volume":"36","author":"Gajski","year":"2013","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/S0196-9781(03)00194-3","article-title":"In vitro activities of native and designed peptide antibiotics against drug sensitive and resistant tumor cell lines","volume":"24","author":"Kim","year":"2003","journal-title":"Peptides"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"505","DOI":"10.3892\/or.2013.2861","article-title":"Effect of StarD13 on colorectal cancer proliferation, motility and invasion","volume":"31","author":"Nasrallah","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5371","DOI":"10.2147\/OTT.S170775","article-title":"STARD13 is positively correlated with good prognosis and enhances 5-FU sensitivity via suppressing cancer stemness in hepatocellular carcinoma cells","volume":"11","author":"Gao","year":"2018","journal-title":"Onco. Targets Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4625","DOI":"10.3892\/ol.2017.6825","article-title":"Homeobox B4 inhibits breast cancer cell migration by directly binding to StAR-related lipid transfer domain protein 13","volume":"14","author":"Zhou","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_50","first-page":"1409","article-title":"Targeting of TLE3 by miR-3677 in human breast cancer promotes cell proliferation, migration and invasion","volume":"19","author":"Peng","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/s13046-016-0426-8","article-title":"TLE3 represses colorectal cancer proliferation by inhibiting MAPK and AKT signaling pathways","volume":"35","author":"Yang","year":"2016","journal-title":"J. Eep. Clin. Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/B978-0-12-381298-8.00027-7","article-title":"Measurement of constitutive MAPK and PI3K\/AKT signaling activity in human cancer cell lines","volume":"484","author":"Paraiso","year":"2010","journal-title":"Methods Enzymol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s13578-019-0361-4","article-title":"Signaling pathways involved in colorectal cancer progression","volume":"9","author":"Koveitypour","year":"2019","journal-title":"Cell Biosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1158\/0008-5472.CAN-17-2683","article-title":"RNF6 promotes colorectal cancer by activating the Wnt\/\u03b2-catenin pathway via ubiquitination of TLE3","volume":"78","author":"Liu","year":"2018","journal-title":"Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1134\/S0026893315040044","article-title":"Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer","volume":"49","author":"Fedorova","year":"2015","journal-title":"Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Sen, T., Sen, N., Noordhuis, M.G., Ravi, R., Wu, T.C., Ha, P.K., Sidransky, D., and Hoque, M.O. (2012). OGDHL is a modifier of AKT-dependent signaling and NF-\u03baB function. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048770"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4657","DOI":"10.1016\/j.bmcl.2013.06.005","article-title":"Improving the antibacterial activity and selectivity of an ultra short peptide by hydrophobic and hydrophilic amino acid stretches","volume":"23","author":"Anunthawan","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/rcm.2898","article-title":"Evaluation of sample fractionation using micro-scale liquid-phase isoelectric focusing on mass spectrometric identification and quantitation of proteins in a SILAC experiment","volume":"21","author":"Thorsell","year":"2007","journal-title":"Rapid Commun Mass Spectrom."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3551","DOI":"10.1002\/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2","article-title":"Probability-based protein identification by searching sequence databases using mass spectrometry data","volume":"20","author":"Perkins","year":"1999","journal-title":"Electrophoresis"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Ochs, M.F., Casagrande, J.T., and Davuluri, R.V. (2010). MeV: MultiExperiment viewer. Biomedical Informatics for Cancer Research, Springer.","DOI":"10.1007\/978-1-4419-5714-6"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhang, Y., Zhou, R., Dossa, K., Yu, J., Li, D., Liu, A., Mmadi, M.A., Zhang, X., and You, J. (2018). Identification and characterization of the bZIP transcription factor family and its expression in response to abiotic stresses in sesame. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200850"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1093\/nar\/gkw1138","article-title":"PANTHER version 11: Expanded annotation data from gene ontology and reactome pathways, and data analysis tool enhancements","volume":"45","author":"Mi","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1093\/nar\/gkv1277","article-title":"STITCH 5: Augmenting protein-chemical interaction networks with tissue and affinity data","volume":"44","author":"Szklarczyk","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/4\/1426\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:23:29Z","timestamp":1760135009000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/4\/1426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,20]]},"references-count":65,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["molecules27041426"],"URL":"https:\/\/doi.org\/10.3390\/molecules27041426","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,20]]}}}