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Journal of Cancer Research and Clinical Oncology

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05.05.2022 | Original Article – Cancer Research

Regulatory network identified by pulmonary transcriptome and proteome profiling reveals extensive change of tumor-related genes in microRNA-21 knockout mice

verfasst von: Ge Luan, Ming Wang, Jing Yuan, Xiangting Bu, Jing Song, Chengshuo Wang, Luo Zhang

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 8/2022

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Abstract

Purpose

MicroRNA-21 (miR-21) is a well-known oncomiR and plays key roles in regulating various biological processes related to pulmonary diseases, especially lung carcinoma. The regulatory roles and downstream targets of miR-21 remain far from well understood. We aimed to identify miR-21–gene regulatory network in lung tissue.

Methods

Transcriptome and proteome analyses were performed on lung tissues from miR-21 knockout (KO) mice and their wildtype (WT) littermates. Differentially expressed genes (DEGs) and proteins (DEPs) between miR-21KO and WT were analyzed, and correlation analysis was performed between transcriptional and translational level. DEPs were used for prediction of miR-21 target genes and construction of co-expression network.

Results

Comparing with WT mice, 820 DEGs and 623 DEPs were identified in lung tissues of miR-21KO mice. Upregulated DEGs and DEPs were both significantly enriched in pathways of metabolism of xenobiotics by cytochrome P450, drug metabolism, and chemical carcinogenesis. Of the 31 molecules commonly identified in DEGs and DEPs, 9 upregulated genes were tumor suppressor genes while 8 downregulated genes were oncogenes, and 12 genes showed closely positive correlation between mRNA and protein expression. Real-time PCR validation results were consistent with the omics data. Among the upregulated DEPs in miR-21KO mice, 21 genes were predicted as miR-21 targets. The miR-21 regulatory network was constructed by target genes and their highly co-expressed proteins, which identified the miR-21 target Itih4 as a hub gene.

Conclusion

MiR-21–gene regulatory network was constructed in mouse lung tissue. MiR-21KO resulted in extensive upregulation of tumor suppressor genes and downregulation of oncogenes.

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Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297. https://doi.org/10.1016/s0092-8674(04)00045-5CrossRefPubMed

Bica-Pop C, Cojocneanu-Petric R, Magdo L, Raduly L, Gulei D, Berindan-Neagoe I (2018) Overview upon miR-21 in lung cancer: focus on NSCLC. Cell Mol Life Sci 75:3539–3551. https://doi.org/10.1007/s00018-018-2877-xCrossRefPubMed

Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, Clark NR, Ma’ayan A (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14:128. https://doi.org/10.1186/1471-2105-14-128CrossRefPubMedPubMedCentral

Chen B, Chen X, Wu X, Wang X, Wang Y, Lin TY, Kurata J, Wu J, Vonderfecht S, Sun G, Huang H, Yee JK, Hu J, Lin RJ (2015) Disruption of microRNA-21 by TALEN leads to diminished cell transformation and increased expression of cell-environment interaction genes. Cancer Lett 356:506–516. https://doi.org/10.1016/j.canlet.2014.09.034CrossRefPubMed

Crawford DR, Ilic Z, Guest I, Milne GL, Hayes JD, Sell S (2017) Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice. Carcinogenesis 38:717–727. https://doi.org/10.1093/carcin/bgx048CrossRefPubMedPubMedCentral

Dan T, Shastri AA, Palagani A, Buraschi S, Neill T, Savage JE, Kapoor A, DeAngelis T, Addya S, Camphausen K, Iozzo RV, Simone NL (2021) miR-21 plays a dual role in tumor formation and cytotoxic response in breast tumors. Cancers (basel). https://doi.org/10.3390/cancers13040888CrossRef

Elfaki I, Mir R, Almutairi FM, Duhier FMA (2018) Cytochrome P450: polymorphisms and roles in cancer, diabetes and atherosclerosis. Asian Pac J Cancer Prev 19:2057–2070. https://doi.org/10.22034/APJCP.2018.19.8.2057CrossRefPubMedPubMedCentral

Gao L, Zeng H, Zhang T, Mao C, Wang Y, Han Z, Chen K, Zhang J, Fan Y, Gu J, Wang C (2019) MicroRNA-21 deficiency attenuated atherogenesis and decreased macrophage infiltration by targeting Dusp-8. Atherosclerosis 291:78–86. https://doi.org/10.1016/j.atherosclerosis.2019.10.003CrossRefPubMed

Hama K, Fujiwara Y, Hayama T, Ozawa T, Nozawa K, Matsuda K, Hashiguchi Y, Yokoyama K (2021) Very long-chain fatty acids are accumulated in triacylglycerol and nonesterified forms in colorectal cancer tissues. Sci Rep 11:6163. https://doi.org/10.1038/s41598-021-85603-wCrossRefPubMedPubMedCentral

Hatley ME, Patrick DM, Garcia MR, Richardson JA, Bassel-Duby R, van Rooij E, Olson EN (2010) Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 18:282–293. https://doi.org/10.1016/j.ccr.2010.08.013CrossRefPubMedPubMedCentral

Huang M, Zhang W, Zhao B, Li L (2019) Relationship between inter-alpha-trypsin inhibitor heavy chain 4 and ovarian cancer. Chin J Cancer Res 31:955–964. https://doi.org/10.21147/j.issn.1000-9604.2019.06.11CrossRefPubMedPubMedCentral

Hukkanen J, Pelkonen O, Hakkola J, Raunio H (2002) Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit Rev Toxicol 32:391–411. https://doi.org/10.1080/20024091064273CrossRefPubMed

Javanmardi S, Aghamaali MR, Abolmaali SS, Mohammadi S, Tamaddon AM (2017) miR-21, an oncogenic target miRNA for cancer therapy: molecular mechanisms and recent advancements in chemo and radio-resistance. Curr Gene Ther 16:375–389. https://doi.org/10.2174/1566523217666170102105119CrossRefPubMed

Jiang C, Guo Y, Yu H, Lu S, Meng L (2019) Pleiotropic microRNA-21 in pulmonary remodeling: novel insights for molecular mechanism and present advancements. Allergy Asthma Clin Immunol 15:33. https://doi.org/10.1186/s13223-019-0345-2CrossRefPubMedPubMedCentral

Kim RY, Sunkara KP, Bracke KR, Jarnicki AG, Donovan C, Hsu AC, Ieni A, Beckett EL, Galvao I, Wijnant S, Ricciardolo FL, Di Stefano A, Haw TJ, Liu G, Ferguson AL, Palendira U, Wark PA, Conickx G, Mestdagh P, Brusselle GG, Caramori G, Foster PS, Horvat JC, Hansbro PM (2021) A microRNA-21- mediated SATB1/S100A9/NF-kappaB axis promotes chronic obstructive pulmonary disease pathogenesis. Sci Transl Med 13:eaav7223. https://doi.org/10.1126/scitranslmed.aav7223CrossRefPubMed

Kumarswamy R, Volkmann I, Thum T (2011) Regulation and function of miRNA-21 in health and disease. RNA Biol 8:706–713. https://doi.org/10.4161/rna.8.5.16154CrossRefPubMedPubMedCentral

Lee EJ, Yang SH, Kim KJ, Cha H, Lee SJ, Kim JH, Song J, Chun KH, Seong J (2018) Inter-alpha inhibitor H4 as a potential biomarker predicting the treatment outcomes in patients with hepatocellular carcinoma. Cancer Res Treat 50:646–657. https://doi.org/10.4143/crt.2016.550CrossRefPubMed

Li J, Ramani K, Sun Z, Zee C, Grant EG, Yang H, Xia M, Oh P, Ko K, Mato JM, Lu SC (2010) Forced expression of methionine adenosyltransferase 1A in human hepatoma cells suppresses in vivo tumorigenicity in mice. Am J Pathol 176:2456–2466. https://doi.org/10.2353/ajpath.2010.090810CrossRefPubMedPubMedCentral

Li L, Wei Y, Van Winkle L, Zhang QY, Zhou X, Hu J, Xie F, Kluetzman K, Ding X (2011) Generation and characterization of a Cyp2f2-null mouse and studies on the role of CYP2F2 in naphthalene-induced toxicity in the lung and nasal olfactory mucosa. J Pharmacol Exp Ther 339:62–71. https://doi.org/10.1124/jpet.111.184671CrossRefPubMedPubMedCentral

Li S, Zeng X, Ma R, Wang L (2018) MicroRNA-21 promotes the proliferation, migration and invasion of non-small cell lung cancer A549 cells by regulating autophagy activity via AMPK/ULK1 signaling pathway. Exp Ther Med 16:2038–2045. https://doi.org/10.3892/etm.2018.6370CrossRefPubMedPubMedCentral

Li H, Zhao J, Jia X, Zhang Y, Du Y, Li H, Ma L, Huang J (2020) miR-21 promotes growth, invasion and migration of lung cancer cells by AKT/P-AKT/cleaved-caspase 3/MMP-2/MMP-9 signaling pathway. Int J Clin Exp Pathol 13:692–700PubMedPubMedCentral

Li W, Qiu C, Wang S, Wu L, Zhao T (2021) Inhibitory effect of glutathione S-transferase A3 in the progression of cutaneous squamous cell carcinoma. J Cosmet Dermatol 20:2287–2295. https://doi.org/10.1111/jocd.13806CrossRefPubMed

Liu J, Ke F, Chen T, Zhou Q, Weng L, Tan J, Shen W, Li L, Zhou J, Xu C, Cheng H, Zhou J (2020) MicroRNAs that regulate PTEN as potential biomarkers in colorectal cancer: a systematic review. J Cancer Res Clin Oncol 146:809–820. https://doi.org/10.1007/s00432-020-03172-3CrossRefPubMed

Lu TX, Munitz A, Rothenberg ME (2009) MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J Immunol 182:4994–5002. https://doi.org/10.4049/jimmunol.0803560CrossRefPubMed

Ma X, Kumar M, Choudhury SN, Becker Buscaglia LE, Barker JR, Kanakamedala K, Liu MF, Li Y (2011) Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis. Proc Natl Acad Sci USA 108:10144–10149. https://doi.org/10.1073/pnas.1103735108CrossRefPubMedPubMedCentral

Noh CK, Kim SS, Kim DK, Lee HY, Cho HJ, Yoon SY, Lee GH, Hyun SA, Kim YJ, Kim HJ, Hwang JA, Ahn SJ, Shin SJ, Lee KM, Yoo BM, Cho SW, Cheong JY (2014) Inter-alpha-trypsin inhibitor heavy chain H4 as a diagnostic and prognostic indicator in patients with hepatitis B virus-associated hepatocellular carcinoma. Clin Biochem 47:1257–1261. https://doi.org/10.1016/j.clinbiochem.2014.05.002CrossRefPubMed

Osman A (2012) MicroRNAs in health and disease—basic science and clinical applications. Clin Lab 58:393–402PubMed

Paredes F, Sheldon K, Lassegue B, Williams HC, Faidley EA, Benavides GA, Torres G, Sanhueza-Olivares F, Yeligar SM, Griendling KK, Darley-Usmar V, San Martin A (2018) Poldip2 is an oxygen-sensitive protein that controls PDH and alphaKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer. Proc Natl Acad Sci USA 115:1789–1794. https://doi.org/10.1073/pnas.1720693115CrossRefPubMedPubMedCentral

Poe AJ, Kulkarni M, Leszczynska A, Tang J, Shah R, Jami-Alahmadi Y, Wang J, Kramerov AA, Wohlschlegel J, Punj V, Ljubimov AV, Saghizadeh M (2020) Integrated transcriptome and proteome analyses reveal the regulatory role of miR-146a in human limbal epithelium via notch signaling. Cells. https://doi.org/10.3390/cells9102175CrossRefPubMedPubMedCentral

Pu M, Chen J, Tao Z, Miao L, Qi X, Wang Y, Ren J (2019) Regulatory network of miRNA on its target: coordination between transcriptional and post-transcriptional regulation of gene expression. Cell Mol Life Sci 76:441–451. https://doi.org/10.1007/s00018-018-2940-7CrossRefPubMed

Sayed D, Abdellatif M (2011) MicroRNAs in development and disease. Physiol Rev 91:827–887. https://doi.org/10.1152/physrev.00006.2010CrossRefPubMed

Shen H, Zhu F, Liu J, Xu T, Pei D, Wang R, Qian Y, Li Q, Wang L, Shi Z, Zheng J, Chen Q, Jiang B, Shu Y (2014) Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer. PLoS One 9:e103305. https://doi.org/10.1371/journal.pone.0103305CrossRefPubMedPubMedCentral

Shi C, Yang Y, Xia Y, Okugawa Y, Yang J, Liang Y, Chen H, Zhang P, Wang F, Han H, Wu W, Gao R, Gasche C, Qin H, Ma Y, Goel A (2016) Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer. Gut 65:1470–1481. https://doi.org/10.1136/gutjnl-2014-308455CrossRefPubMed

Song L, Liu S, Zhang L, Yao H, Gao F, Xu D, Li Q (2016) MiR-21 modulates radiosensitivity of cervical cancer through inhibiting autophagy via the PTEN/Akt/HIF-1alpha feedback loop and the Akt-mTOR signaling pathway. Tumour Biol 37:12161–12168. https://doi.org/10.1007/s13277-016-5073-3CrossRefPubMed

Song Y, Zuo Y, Qian XL, Chen ZP, Wang SK, Song L, Peng LP (2017) Inhibition of microRNA-21-5p promotes the radiation sensitivity of non-small cell lung cancer through HMSH2. Cell Physiol Biochem 43:1258–1272. https://doi.org/10.1159/000481839CrossRefPubMed

Sticht C, De La Torre C, Parveen A, Gretz N (2018) miRWalk: an online resource for prediction of microRNA binding sites. PLoS One 13:e0206239. https://doi.org/10.1371/journal.pone.0206239CrossRefPubMedPubMedCentral

Sun YV, Hu YJ (2016) Integrative analysis of multi-omics data for discovery and functional studies of complex human diseases. Adv Genet 93:147–190. https://doi.org/10.1016/bs.adgen.2015.11.004CrossRefPubMedPubMedCentral

Vicinus B, Rubie C, Faust SK, Frick VO, Ghadjar P, Wagner M, Graeber S, Schilling MK (2012) miR-21 functionally interacts with the 3’UTR of chemokine CCL20 and down-regulates CCL20 expression in miR-21 transfected colorectal cancer cells. Cancer Lett 316:105–112. https://doi.org/10.1016/j.canlet.2011.10.031CrossRefPubMed

Wang Q, Zhang L (2019) Possible molecular mechanisms for the roles of microrna-21 played in lung cancer. Technol Cancer Res Treat 18:1533033819875130. https://doi.org/10.1177/1533033819875130CrossRefPubMed

Zhong Z, Dong Z, Yang L, Gong Z (2012) miR-21 induces cell cycle at S phase and modulates cell proliferation by down-regulating hMSH2 in lung cancer. J Cancer Res Clin Oncol 138:1781–1788. https://doi.org/10.1007/s00432-012-1287-yCrossRefPubMed

Titel: Regulatory network identified by pulmonary transcriptome and proteome profiling reveals extensive change of tumor-related genes in microRNA-21 knockout mice
verfasst von: Ge Luan
Ming Wang
Jing Yuan
Xiangting Bu
Jing Song
Chengshuo Wang
Luo Zhang
Publikationsdatum: 05.05.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 8/2022
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-022-03967-6

Springer Medizin

Regulatory network identified by pulmonary transcriptome and proteome profiling reveals extensive change of tumor-related genes in microRNA-21 knockout mice