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DOI: 10.1055/a-1989-1918
E2F2 Promotes Wound Healing of Diabetic Foot Ulcer by Regulating CDCA7L Transcription
Funding This research was funded by grants from the Hunan Provincial Health Commission (Grant No. 20201906), the Hunan Provincial Health and Family Planning Commission (Grant No. A2017018), and the Hunan Provincial Clinical Medical Research Center (Grant No. 2021SK4030).Abstract
Objective The E2F2 transcription factor can accelerate cell proliferation and wound healing. However, its mechanism of action in a diabetic foot ulcer (DFU) remains unclear. Therefore, this study explores the influence of E2F2 on wound healing in DFU by examining cell division cycle-associated 7-like (CDCA7L) expression.
Methods CDCA7L and E2F2 expression in DFU tissues were analyzed with databases. CDCA7L and E2F2 expression were altered in human umbilical vein endothelial cells (HUVECs) and spontaneously transformed human keratinocyte cell culture (HaCaT) cells. Cell viability, migration, colony formation, and angiogenesis were evaluated. Binding of E2F2 to the CDCA7L promoter was examined. Subsequently, a diabetes mellitus (DM) mouse model was established and treated with full-thickness excision followed by CDCA7L overexpression. Wound healing in these mice was observed and recorded, and vascular endothelial growth factor receptor 2 (VEGFR2) and hematopoietic progenitor cell antigen CD34 (CD34) expression were determined. E2F2 and CDCA7L expression levels in cells and mice were evaluated. The expression of growth factors was tested.
Results CDCA7L expression was downregulated in DFU tissues and wound tissues from DM mice. Mechanistically, E2F2 bound to the CDCA7L promoter to upregulate CDCA7L expression. E2F2 overexpression enhanced viability, migration, and growth factor expression in HaCaT cells and HUVECs, and augmented HUVEC angiogenesis and HaCaT cell proliferation, which was nullified by silencing CDCA7L. In DM mice, CDCA7L overexpression facilitated wound healing and elevated the expression level of growth factors.
Conclusions E2F2 facilitated cell proliferation and migration and fostered wound healing in DFU cells through binding to the CDCA7L promoter.
Publication History
Received: 28 July 2022
Received: 17 November 2022
Accepted: 17 November 2022
Article published online:
09 March 2023
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References
- 1 Saeedi P, Petersohn I, Salpea P. et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 2019; 157: 107843 DOI: 10.1016/j.diabres.2019.107843.
- 2 Patel S, Srivastava S, Singh MR. et al. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother 2019; 112: 108615 DOI: 10.1016/j.biopha.2019.108615.
- 3 Schaper NC, Van Netten JJ, Apelqvist J. et al. Prevention and management of foot problems in diabetes: a Summary Guidance for Daily Practice 2015, based on the IWGDF Guidance Documents. Diabetes Metab Res Rev 2016; 32: 7-15 DOI: 10.1002/dmrr.2695.
- 4 van Netten JJ, Raspovic A, Lavery LA. et al. Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review. Diabetes Metab Res Rev 2020; 36: e3270 DOI: 10.1002/dmrr.3270.
- 5 Okonkwo UA, DiPietro LA. Diabetes and Wound Angiogenesis. Int J Mol Sci 2017; 18 DOI: 10.3390/ijms18071419.
- 6 Ji QK, Ma JW, Liu RH. et al. CDCA7L promotes glioma proliferation by targeting CCND1 and predicts an unfavorable prognosis. Mol Med Rep 2019; 20: 1149-1156 DOI: 10.3892/mmr.2019.10349.
- 7 Shen FZ, Li XS, Ma JW. et al. Cell division cycle associated 7 like predicts unfavorable prognosis and promotes invasion in glioma. Pathol Res Pract 2019; 215: 50-56 DOI: 10.1016/j.prp.2018.10.023.
- 8 Huang A, Ho CS, Ponzielli R. et al. Identification of a novel c-Myc protein interactor, JPO2, with transforming activity in medulloblastoma cells. Cancer Res 2005; 65: 5607-5619 DOI: 10.1158/0008-5472.CAN-05-0500.
- 9 Chan TS, Hawkins C, Krieger JR. et al. JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma. Cancer Res 2016; 76: 2802-2812 DOI: 10.1158/0008-5472.CAN-15-2194.
- 10 Delgado I, Fresnedo O, Iglesias A. et al. A role for transcription factor E2F2 in hepatocyte proliferation and timely liver regeneration. Am J Physiol Gastrointest Liver Physiol 2011; 301: G20-G31 DOI: 10.1152/ajpgi.00481.2010.
- 11 Iglesias-Ara A, Zenarruzabeitia O, Buelta L. et al. E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution. Cell Death Differ 2015; 22: 1577-1589 DOI: 10.1038/cdd.2015.4.
- 12 Zeng L, Xiao Q, Chen M. et al. Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis. Circulation 2013; 127: 1712-1722 DOI: 10.1161/CIRCULATIONAHA.112.001337.
- 13 Huang X, Liang P, Jiang B. et al. Hyperbaric oxygen potentiates diabetic wound healing by promoting fibroblast cell proliferation and endothelial cell angiogenesis. Life Sci 2020; 259: 118246 DOI: 10.1016/j.lfs.2020.118246.
- 14 Huang X, Sun J, Chen G. et al. Resveratrol Promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc Signaling Pathway-Mediated Angiogenesis. Front Pharmacol 2019; 10: 421 DOI: 10.3389/fphar.2019.00421.
- 15 Gao B, Wang X, Wang M. et al. From single to a dual-gene delivery nanosystem: coordinated expression matters for boosting the neovascularization in vivo. Biomater Sci 2020; 8: 2318-2328 DOI: 10.1039/c9bm02000d.
- 16 Maatouk B, Jaffa MA, Karam M. et al. Sulfated alginate/polycaprolactone double-emulsion nanoparticles for enhanced delivery of heparin-binding growth factors in wound healing applications. Colloids Surf B Biointerfaces 2021; 208: 112105 DOI: 10.1016/j.colsurfb.2021.112105.
- 17 Zhang HC, Wen T, Cai YZ. Overexpression of miR-146a promotes cell proliferation and migration in a model of diabetic foot ulcers by regulating the AKAP12 axis. Endocr J 2021; DOI: 10.1507/endocrj.EJ21-0177.
- 18 Castro-Mondragon JA, Riudavets-Puig R, Rauluseviciute I. et al. JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles. Nucleic Acids Res 2022; 50: D165-D173 DOI: 10.1093/nar/gkab1113.
- 19 Ban E, Jeong S, Park M. et al. Accelerated wound healing in diabetic mice by miRNA-497 and its anti-inflammatory activity. Biomed Pharmacother 2020; 121: 109613 DOI: 10.1016/j.biopha.2019.109613.
- 20 Zhao Y, Wang Q, Yan S. et al. Bletilla striata Polysaccharide Promotes Diabetic Wound Healing Through Inhibition of the NLRP3 Inflammasome. Front Pharmacol 2021; 12: 659215 DOI: 10.3389/fphar.2021.659215.
- 21 Guo X, Mu D, Gao F. Efficacy and safety of acellular dermal matrix in diabetic foot ulcer treatment: A systematic review and meta-analysis. Int J Surg 2017; 40: 1-7 DOI: 10.1016/j.ijsu.2017.02.008.
- 22 Qing C. The molecular biology in wound healing & non-healing wound. Chin J Traumatol 2017; 20: 189-193 DOI: 10.1016/j.cjtee.2017.06.001.
- 23 Weinhold N, Meissner T, Johnson DC. et al. The 7p15.3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells. Haematologica 2015; 100: e110-e113 DOI: 10.3324/haematol.2014.118786.
- 24 Lin TP, Li J, Li Q. et al. R1 Regulates Prostate Tumor Growth and Progression By Transcriptional Suppression of the E3 Ligase HUWE1 to Stabilize c-Myc. Mol Cancer Res 2018; 16: 1940-1951 DOI: 10.1158/1541-7786.MCR-16-0346.
- 25 Chen K, Ou XM, Wu JB. et al. Transcription factor E2F-associated phosphoprotein (EAPP), RAM2/CDCA7L/JPO2 (R1), and simian virus 40 promoter factor 1 (Sp1) cooperatively regulate glucocorticoid activation of monoamine oxidase B. Mol Pharmacol 2011; 79: 308-317 DOI: 10.1124/mol.110.067439.
- 26 Iglesias A, Murga M, Laresgoiti U. et al. Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. J Clin Invest 2004; 113: 1398-1407 DOI: 10.1172/JCI18879.
- 27 Muniandy K, Gothai S, Tan WS. et al. In Vitro Wound Healing Potential of Stem Extract of Alternanthera sessilis. Evid Based Complement Alternat Med 2018; 2018: 3142073 DOI: 10.1155/2018/3142073.
- 28 Wang A, Toma MA, Ma J. et al. Circular RNA hsa_circ_0084443 Is Upregulated in Diabetic Foot Ulcer and Modulates Keratinocyte Migration and Proliferation. Adv Wound Care (New Rochelle) 2020; 9: 145-160 DOI: 10.1089/wound.2019.0956.
- 29 Tian Y, Huang C, Zhang H. et al. CDCA7L promotes hepatocellular carcinoma progression by regulating the cell cycle. Int J Oncol 2013; 43: 2082-2090 DOI: 10.3892/ijo.2013.2142.
- 30 Xuan C, Jin M, Gao Y. et al. miR-218 suppresses the proliferation of osteosarcoma through downregulation of E2F2. Oncol Lett 2019; 17: 571-577 DOI: 10.3892/ol.2018.9576.
- 31 Yang PL, Wang JS, Cheng XM. et al. PPAR-gamma Ligand Inhibits Nasopharyngeal Carcinoma Cell Proliferation and Metastasis by Regulating E2F2. PPAR Res 2019; 2019: 8679271 DOI: 10.1155/2019/8679271.
- 32 Ding A, Bian YY, Zhang ZH. SP1/TGFbeta1/SMAD2 pathway is involved in angiogenesis during osteogenesis. Mol Med Rep 2020; 21: 1581-1589 DOI: 10.3892/mmr.2020.10965.
- 33 Zhang Q, Li T, Wang Z. et al. lncRNA NR2F1-AS1 promotes breast cancer angiogenesis through activating IGF-1/IGF-1R/ERK pathway. J Cell Mol Med 2020; 24: 8236-8247 DOI: 10.1111/jcmm.15499.
- 34 Zhao J, Du P, Cui P. et al. LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer. Oncogene 2018; 37: 4094-4109 DOI: 10.1038/s41388-018-0250-z.
- 35 Hsieh MJ, Chiu TJ, Lin YC. et al. Inactivation of APC Induces CD34 Upregulation to Promote Epithelial-Mesenchymal Transition and Cancer Stem Cell Traits in Pancreatic Cancer. Int J Mol Sci 2020; 21 DOI: 10.3390/ijms21124473.
- 36 Zhang Q, Lu S, Li T. et al. ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. J Exp Clin Cancer Res 2019; 38: 173 DOI: 10.1186/s13046-019-1156-5.