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Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

RBM3 Accelerates Wound Healing of Skin in Diabetes through ERK1/2 Signaling

Author(s): Jianguo Feng*, Menghong Long, Xin Zhao, Pijun Yan, Yunxiao Lin, Maohua Wang* and Wenhua Huang*

Volume 17, 2024

Published on: 13 October, 2023

Article ID: e18761429260980 Pages: 11

DOI: 10.2174/0118761429260980231005105929

open_access

Open Access Journals Promotions 2
Abstract

Background: With the increasing risk of infections and other serious complications, the underlying molecular mechanism of wound healing impairment in diabetes deserves attention. Cold shock proteins (CSPs), including CIRP and RBM3 are highly expressed in the skin; however, it is unknown whether CSPs are involved in the wound-healing impairment of diabetic skin.

Objectives: The objective of this study is to investigate the effects of RBM3 on skin wound healing in diabetes.

Methods: In vitro experiments, western blot assay was used to test the levels of proteins in HaCaT cells treated with different concentrations of glucose. RBM3 was over-expressed in HaCaT cells using lentivirus particles. Cell viability was analyzed by Cell-Counting Kit-8 assay and colony formation assay. The migration of HaCaT cells at different concentrations of glucose was evaluated by wound healing assay. In vivo experiments, the mouse model of diabetes was established by intraperitoneal injection of streptozotocin. Four weeks later, the mice were anesthetized by intraperitoneal injection of pentobarbital sodium for skin tissue collection or wound healing experiments. RBM3 knockout mice were established by removing exons 2–6 using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technique and then used in skin wound healing experiments with or without diabetic stress.

Results: In this study, the expression of RBM3, rather than CIRP, was altered in the skin of diabetic specimens, and the RBM3’s overexpression accelerated the cell viability and proliferation of HaCaT cells under high glucose conditions. RBM3 deficiency caused delayed wound healing in RBM3 knockout in diabetic conditions. Moreover. RBM3 enhanced the ERK1/2 signaling pathway, and its inhibitor FR180204 blocked the beneficial effect of RBM3 overexpression on skin wound healing in diabetes.

Conclusion: RBM3 activated the ERK1/2 signal to facilitate skin wound healing in diabetes, offering a novel therapeutic target for its treatment.

Keywords: Cold shock proteins, Cell migration, Diabetes, ERK1/2, RBM3, Wound healing.

[1]
Okonkwo, U.; DiPietro, L. Diabetes and wound angiogenesis. Int. J. Mol. Sci., 2017, 18(7), 1419.
[http://dx.doi.org/10.3390/ijms18071419] [PMID: 28671607]
[2]
Pop, M.A.; Almquist, B.D. Biomaterials: A potential pathway to healing chronic wounds? Exp. Dermatol., 2017, 26(9), 760-763.
[http://dx.doi.org/10.1111/exd.13290] [PMID: 28094868]
[3]
Barman, P.K.; Koh, T.J. Macrophage dysregulation and impaired skin wound healing in diabetes. Front. Cell Dev. Biol., 2020, 8, 528.
[http://dx.doi.org/10.3389/fcell.2020.00528] [PMID: 32671072]
[4]
Spampinato, S.F.; Caruso, G.I.; De Pasquale, R.; Sortino, M.A.; Merlo, S. The treatment of impaired wound healing in diabetes: Looking among old drugs. Pharmaceuticals, 2020, 13(4), 60.
[http://dx.doi.org/10.3390/ph13040060] [PMID: 32244718]
[5]
Deng, L.; Du, C.; Song, P.; Chen, T.; Rui, S.; Armstrong, D.G.; Deng, W. The role of oxidative stress and antioxidants in diabetic wound healing. Oxid. Med. Cell. Longev., 2021, 2021, 1-11.
[http://dx.doi.org/10.1155/2021/8852759] [PMID: 33628388]
[6]
Zhang, J.; Wang, X.; Vikash, V.; Ye, Q.; Wu, D.; Liu, Y.; Dong, W. ROS and ROS-mediated cellular signaling. Oxid. Med. Cell. Longev., 2016, 2016, 1-18.
[http://dx.doi.org/10.1155/2016/4350965] [PMID: 26998193]
[7]
Atalay, M.; Oksala, N.; Lappalainen, J.; Laaksonen, D.; Sen, C.; Roy, S. Heat shock proteins in diabetes and wound healing. Curr. Protein Pept. Sci., 2009, 10(1), 85-95.
[http://dx.doi.org/10.2174/138920309787315202] [PMID: 19275675]
[8]
Zhong, X.; Wang, T.; Xie, Y.; Wang, M.; Zhang, W.; Dai, L.; Lai, J.; Nie, X.; He, X.; Madhusudhan, T.; Zeng, H.; Wang, H. Activated protein C ameliorates diabetic cardiomyopathy via modulating OTUB1/YB-1/MEF2B axis. Front. Cardiovasc. Med., 2021, 8, 758158.
[http://dx.doi.org/10.3389/fcvm.2021.758158] [PMID: 34778410]
[9]
Higashitsuji, H.; Fujita, T.; Higashitsuji, H.; Fujita, J. Mammalian cold-inducible RNA-binding protein facilitates wound healing through activation of AMP-activated protein kinase. Biochem. Biophys. Res. Commun., 2020, 533(4), 1191-1197.
[http://dx.doi.org/10.1016/j.bbrc.2020.10.004] [PMID: 33041006]
[10]
Idrovo, J.P.; Jacob, A.; Yang, W.L.; Wang, Z.; Yen, H.T.; Nicastro, J.; Coppa, G.F.; Wang, P. A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing. Int. J. Mol. Med., 2016, 37(2), 423-428.
[http://dx.doi.org/10.3892/ijmm.2016.2451] [PMID: 26743936]
[11]
Sureban, S.M.; Ramalingam, S.; Natarajan, G.; May, R.; Subramaniam, D.; Bishnupuri, K.S.; Morrison, A.R.; Dieckgraefe, B.K.; Brackett, D.J.; Postier, R.G.; Houchen, C.W.; Anant, S. Translation regulatory factor RBM3 is a proto-oncogene that prevents mitotic catastrophe. Oncogene, 2008, 27(33), 4544-4556.
[http://dx.doi.org/10.1038/onc.2008.97] [PMID: 18427544]
[12]
Chip, S.; Zelmer, A.; Ogunshola, O.O.; Felderhoff-Mueser, U.; Nitsch, C.; Bührer, C.; Wellmann, S. The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection. Neurobiol. Dis., 2011, 43(2), 388-396.
[http://dx.doi.org/10.1016/j.nbd.2011.04.010] [PMID: 21527344]
[13]
Peretti, D.; Bastide, A.; Radford, H.; Verity, N.; Molloy, C.; Martin, M.G.; Moreno, J.A.; Steinert, J.R.; Smith, T.; Dinsdale, D.; Willis, A.E.; Mallucci, G.R. RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature, 2015, 518(7538), 236-239.
[http://dx.doi.org/10.1038/nature14142] [PMID: 25607368]
[14]
Cui, Z.; Zhang, J.; Bao, G.; Xu, G.; Sun, Y.; Wang, L.; Chen, J.; Jin, H.; Liu, J.; Yang, L.; Feng, G.; Li, W. Spatiotemporal profile and essential role of RBM3 expression after spinal cord injury in adult rats. J. Mol. Neurosci., 2014, 54(2), 252-263.
[http://dx.doi.org/10.1007/s12031-014-0282-y] [PMID: 24668366]
[15]
Zhu, X.; Zelmer, A.; Kapfhammer, J.P.; Wellmann, S. Cold-inducible RBM3 inhibits PERK phosphorylation through cooperation with NF90 to protect cells from endoplasmic reticulum stress. FASEB J., 2016, 30(2), 624-634.
[http://dx.doi.org/10.1096/fj.15-274639] [PMID: 26472337]
[16]
Feng, J.; Pan, W.; Yang, X.; Long, F.; Zhou, J.; Liao, Y.; Wang, M. RBM3 increases cell survival but disrupts tight junction of microvascular endothelial cells in acute lung injury. J. Surg. Res., 2021, 261, 226-235.
[http://dx.doi.org/10.1016/j.jss.2020.12.041] [PMID: 33460967]
[17]
Zhu, X.; Bührer, C.; Wellmann, S. Cold-inducible proteins CIRP and RBM3, a unique couple with activities far beyond the cold. Cell. Mol. Life Sci., 2016, 73(20), 3839-3859.
[http://dx.doi.org/10.1007/s00018-016-2253-7] [PMID: 27147467]
[18]
Gilbert, E.R.; Fu, Z.; Liu, D. Development of a nongenetic mouse model of type 2 diabetes. Exp. Diabetes Res., 2011, 2011, 1-12.
[http://dx.doi.org/10.1155/2011/416254] [PMID: 22164157]
[19]
Ma, P.F.; Jiang, J.; Gao, C.; Cheng, P.P.; Li, J.L.; Huang, X.; Lin, Y.Y.; Li, Q.; Peng, Y.Z.; Cai, M.C.; Shao, W.; Zhu, Q.; Han, S.; Qin, Q.; Xia, J.J.; Qi, Z.Q. Immunosuppressive effect of compound K on islet transplantation in an STZ-induced diabetic mouse model. Diabetes, 2014, 63(10), 3458-3469.
[http://dx.doi.org/10.2337/db14-0012] [PMID: 24834979]
[20]
Bai, Y.; Shi, D.; Lu, H.; Yang, K.; Zhao, H.; Lu, B.; Pang, Z. Hypoglycemic effects of Tibetan medicine Huidouba in STZ-induced diabetic mice and db/db mice. Chin. Herb. Med., 2021, 13(2), 202-209.
[http://dx.doi.org/10.1016/j.chmed.2021.02.001] [PMID: 36117512]
[21]
Feng, J.; Liao, Y.; Xu, X.; Yi, Q.; He, L.; Tang, L. hnRNP A1 promotes keratinocyte cell survival post UVB radiation through PI3K/Akt/mTOR pathway. Exp. Cell Res., 2018, 362(2), 394-399.
[http://dx.doi.org/10.1016/j.yexcr.2017.12.002] [PMID: 29229447]
[22]
Huang, X.; Chen, Y.; Yi, J.; Yi, P.; Jia, J.; Liao, Y.; Feng, J.; Jiang, X. Tetracaine hydrochloride induces cell cycle arrest in melanoma by downregulating hnRNPA1. Toxicol. Appl. Pharmacol., 2022, 434, 115810.
[http://dx.doi.org/10.1016/j.taap.2021.115810] [PMID: 34822839]
[23]
Pilotte, J.; Cunningham, B.A.; Edelman, G.M.; Vanderklish, P.W. Developmentally regulated expression of the cold-inducible RNA-binding motif protein 3 in euthermic rat brain. Brain Res., 2009, 1258, 12-24.
[http://dx.doi.org/10.1016/j.brainres.2008.12.050] [PMID: 19150436]
[24]
Wilkinson, H.N.; Hardman, M.J. Senescence in wound repair: Emerging strategies to target chronic healing wounds. Front. Cell Dev. Biol., 2020, 8, 773.
[http://dx.doi.org/10.3389/fcell.2020.00773] [PMID: 32850866]
[25]
Wang, W.; Zhang, F.; Yan, X.; Tan, Q. Wnt7a regulates high autophagic and inflammatory response of epidermis in high-glucose environment. Burns, 2020, 46(1), 121-127.
[http://dx.doi.org/10.1016/j.burns.2019.07.025] [PMID: 31852613]
[26]
Wang, D.; Jiang, Y.; Li, Z.; Xue, L.; Li, X.; Liu, Y.; Li, C.; Wang, H. The effect of candida albicans on the expression levels of toll-like receptor 2 and interleukin-8 in hacat cells under high- and low-glucose conditions. Indian J. Dermatol., 2018, 63(3), 201-207.
[PMID: 29937555]
[27]
Bhattacharya, S.; Aggarwal, R.; Pal Singh, V.; Ramachandran, S.; Datta, M. Downregulation of mirnas during delayed wound healing in diabetes: role of dicer. Mol. Med., 2015, 21(1), 847-860.
[http://dx.doi.org/10.2119/molmed.2014.00186] [PMID: 26602065]
[28]
Zhuang, R.J.; Ma, J.; Shi, X.; Ju, F.; Ma, S.P.; Wang, L.; Cheng, B.F.; Ma, Y.W.; Wang, M.; Li, T.; Feng, Z.W.; Yang, H.J. Cold-inducible protein RBM3 protects UV irradiation-induced apoptosis in neuroblastoma cells by affecting p38 and JNK pathways and Bcl2 family proteins. J. Mol. Neurosci., 2017, 63(2), 142-151.
[http://dx.doi.org/10.1007/s12031-017-0964-3] [PMID: 28831692]
[29]
Yang, H.J.; Zhuang, R.J.; Li, Y.B.; Li, T.; Yuan, X.; Lei, B.B.; Xie, Y.F.; Wang, M. Cold-inducible protein RBM3 mediates hypothermic neuroprotection against neurotoxin rotenone via inhibition on MAPK signalling. J. Cell. Mol. Med., 2019, 23(10), 7010-7020.
[http://dx.doi.org/10.1111/jcmm.14588] [PMID: 31436914]
[30]
Yang, H.J.; Shi, X.; Ju, F.; Hao, B.N.; Ma, S.P.; Wang, L.; Cheng, B.F.; Wang, M. Cold shock induced protein rbm3 but not mild hypothermia protects human SH-SY5Y neuroblastoma cells from MPP+-induced neurotoxicity. Front. Neurosci., 2018, 12, 298.
[http://dx.doi.org/10.3389/fnins.2018.00298] [PMID: 29773975]
[31]
Wellmann, S.; Truss, M.; Bruder, E.; Tornillo, L.; Zelmer, A.; Seeger, K.; Bührer, C. The RNA-binding protein RBM3 is required for cell proliferation and protects against serum deprivation-induced cell death. Pediatr. Res., 2010, 67(1), 35-41.
[http://dx.doi.org/10.1203/PDR.0b013e3181c13326] [PMID: 19770690]
[32]
Roskoski, R., Jr ERK1/2 MAP kinases: Structure, function, and regulation. Pharmacol. Res., 2012, 66(2), 105-143.
[http://dx.doi.org/10.1016/j.phrs.2012.04.005] [PMID: 22569528]
[33]
Park, J.; Shin, M.S.; Hwang, G.; Yamabe, N.; Yoo, J.E.; Kang, K.; Kim, J.C.; Lee, J.; Ham, J.; Lee, H. Beneficial effects of deoxyshikonin on delayed wound healing in diabetic mice. Int. J. Mol. Sci., 2018, 19(11), 3660.
[http://dx.doi.org/10.3390/ijms19113660] [PMID: 30463303]
[34]
Sinagra, T.; Merlo, S.; Spampinato, S.F.; Pasquale, R.D.; Sortino, M.A. High mobility group box 1 contributes to wound healing induced by inhibition of dipeptidylpeptidase 4 in cultured keratinocytes. Front. Pharmacol., 2015, 6, 126.
[http://dx.doi.org/10.3389/fphar.2015.00126] [PMID: 26136686]
[35]
Jere, S.W.; Houreld, N.N.; Abrahamse, H. Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev., 2019, 50, 52-59.
[http://dx.doi.org/10.1016/j.cytogfr.2019.03.001] [PMID: 30890300]
[36]
Ferry, A.L.; Vanderklish, P.W.; Dupont-Versteegden, E.E. Enhanced survival of skeletal muscle myoblasts in response to overexpression of cold shock protein RBM3. Am. J. Physiol. Cell Physiol., 2011, 301(2), C392-C402.
[http://dx.doi.org/10.1152/ajpcell.00098.2011] [PMID: 21593448]
[37]
Zhao, W.; Xu, D.; Cai, G.; Zhu, X.; Qian, M.; Liu, W.; Cui, Z. Spatiotemporal pattern of RNA-binding motif protein 3 expression after spinal cord injury in rats. Cell. Mol. Neurobiol., 2014, 34(4), 491-499.
[http://dx.doi.org/10.1007/s10571-014-0033-1] [PMID: 24570111]
[38]
Shi, H.; Yao, R.; Lian, S.; Liu, P.; Liu, Y.; Yang, Y.Y.; Yang, H.; Li, S. Regulating glycolysis, the TLR4 signal pathway and expression of RBM3 in mouse liver in response to acute cold exposure. Stress, 2019, 22(3), 366-376.
[http://dx.doi.org/10.1080/10253890.2019.1568987] [PMID: 30821572]

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