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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Evaluation of Serum miR-216a, miR-216b, miR-217, miR-92b, miR-375 and miR-148a as Potential Biomarkers for Acute Pancreatitis and the Role of miR-92b in Attenuating Caerulein-induced Injury and Inflammatory Responses in AR42J Cells

Author(s): Benshen Luo, Chen Wang, Zhengyu Wang, Chuanguo Chen, Xiaozhuang Peng and Qingchun Xu*

Volume 26, Issue 12, 2023

Published on: 21 February, 2023

Page: [2184 - 2193] Pages: 10

DOI: 10.2174/1386207326666230202141348

Price: $65

Abstract

Background: Acute pancreatitis can eventually lead to morbidity and mortality. The present study aimed to identify the differentially expressed microRNAs (miRNAs) that are related to acute pancreatitis and explore the in vitro functional role of miR-92b in acute pancreatitis.

Methods: Bioinformatics analysis was used to identify differentially expressed miRNAs in caerulein- induced acute pancreatitis samples when compared to normal controls. The role of miR-92b in acute pancreatitis was examined by in vitro functional assays.

Results: MiRNA-network analysis revealed 12 miRNAs that function as “core regulatory miRNAs”. Further validation studies revealed that six miRNAs (miR-216a, miR-216b, miR-217, miR- 92b, miR-375 and miR-148a) were differentially expressed in the serum samples from patients with acute pancreatitis. These six miRNAs have fair diagnostic potential for severe acute pancreatitis. Caerulein induced cell injury and inflammatory response and repressed miR-92b expression in AR42J cells. MiR-92b overexpression attenuated caerulein-induced cell injury and inflammatory responses in AR42J cells. Luciferase reporter assay showed that mitogen-activated protein kinase 4 (MAP2K4) was a direct target of miR-92b. MiR-92b overexpression repressed MAP2K4 expression, while caerulein up-regulated MAP2K4 expression in AR42J cells. The rescue experiments showed that enforced expression of MAP2K4 partially reversed the miR-92b-mediated protective effects on caerulein-induced AR42J cell injury.

Conclusion: In conclusion, we identified miR-216a, miR-216b, miR217, miR-92b, miR-375 and miR-148a as new candidate biomarkers for acute pancreatitis. Further in vitro functional studies revealed that miR-92b attenuated caerulein-induced cell injury and inflammatory responses in AJ42R cells partially via targeting MAP2K4.

Graphical Abstract

[1]
Lankisch, P.G.; Apte, M.; Banks, P.A. Acute pancreatitis. Lancet, 2015, 386(9988), 85-96.
[http://dx.doi.org/10.1016/S0140-6736(14)60649-8] [PMID: 25616312]
[2]
Greenberg, J.A.; Hsu, J.; Bawazeer, M.; Marshall, J.; Friedrich, J.O.; Nathens, A.; Coburn, N.; May, G.R.; Pearsall, E.; McLeod, R.S. Clinical practice guideline: Management of acute pancreatitis. Canad. J. Surg., 2016, 59(2), 128-140.
[3]
Mandalia, A.; Wamsteker, E.J.; DiMagno, M.J. Recent advances in understanding and managing acute pancreatitis. F1000 Res., 2018, 7, 959.
[http://dx.doi.org/10.12688/f1000research.14244.1] [PMID: 30026919]
[4]
van Dijk, S.M.; Hallensleben, N.D.L.; van Santvoort, H.C.; Fockens, P.; van Goor, H.; Bruno, M.J.; Besselink, M.G. Acute pancreatitis: Recent advances through randomised trials. Gut, 2017, 66(11), 2024-2032.
[http://dx.doi.org/10.1136/gutjnl-2016-313595] [PMID: 28838972]
[5]
Meher, S.; Mishra, T.S.; Sasmal, P.K.; Rath, S.; Sharma, R.; Rout, B.; Sahu, M.K. Role of biomarkers in diagnosis and prognostic evaluation of acute pancreatitis. J. Biomark., 2015, 2015, 1-13.
[http://dx.doi.org/10.1155/2015/519534] [PMID: 26345247]
[6]
Ambros, V. The functions of animal microRNAs. Nature, 2004, 431(7006), 350-355.
[http://dx.doi.org/10.1038/nature02871] [PMID: 15372042]
[7]
Alles, J.; Fehlmann, T.; Fischer, U.; Backes, C.; Galata, V.; Minet, M.; Hart, M.; Abu-Halima, M.; Grässer, F.A.; Lenhof, H.P.; Keller, A.; Meese, E. An estimate of the total number of true human miRNAs. Nucleic Acids Res., 2019, 47(7), 3353-3364.
[http://dx.doi.org/10.1093/nar/gkz097] [PMID: 30820533]
[8]
Endo, K.; Weng, H.; Kito, N.; Fukushima, Y.; Iwai, N. miR-216a and miR-216b as markers for acute phased pancreatic injury. Biomed. Res., 2013, 34(4), 179-188.
[http://dx.doi.org/10.2220/biomedres.34.179] [PMID: 23995054]
[9]
Kuśnierz-Cabala, B.; Nowak, E.; Sporek, M.; Kowalik, A.; Kuźniewski, M.; Enguita, F.J.; Stępień, E. Serum levels of unique miR-551-5p and endothelial-specific miR-126a-5p allow discrimination of patients in the early phase of acute pancreatitis. Pancreatology, 2015, 15(4), 344-351.
[10]
Lu, X.G.; Kang, X.; Zhan, L.B.; Kang, L.M.; Fan, Z.W.; Bai, L.Z. Circulating miRNAs as biomarkers for severe acute pancreatitis associated with acute lung injury. World J. Gastroenterol., 2017, 23(41), 7440-7449.
[http://dx.doi.org/10.3748/wjg.v23.i41.7440] [PMID: 29151698]
[11]
Miao, B.; Qi, W.J.; Zhang, S.W.; Wang, H.; Wang, C.; Hu, L.; Huang, G.W.; Li, S.R.; Wang, H. miR-148a suppresses autophagy by down-regulation of IL-6/STAT3 signaling in cerulein-induced acute pancreatitis. Pancreatology, 2019, 19(4), 557-565.
[12]
Zhou, W.; Dong, S.; Chen, Z.; Li, X.; Jiang, W. New challenges for microRNAs in acute pancreatitis: Progress and treatment. J. Transl. Med., 2022, 20(1), 192.
[http://dx.doi.org/10.1186/s12967-022-03338-2] [PMID: 35509084]
[13]
Choi, K.; Ratner, N. iGEAK: An interactive gene expression analysis kit for seamless workflow using the R/shiny platform. BMC Genomics, 2019, 20(1), 177.
[http://dx.doi.org/10.1186/s12864-019-5548-x] [PMID: 30841853]
[14]
Fan, Y.; Siklenka, K.; Arora, S.K.; Ribeiro, P.; Kimmins, S.; Xia, J. miRNet-dissecting miRNA-target interactions and functional associations through network-based visual analysis. Nucleic Acids Res., 2016, 44(W1), W135-W141.
[http://dx.doi.org/10.1093/nar/gkw288] [PMID: 27105848]
[15]
Zhang, X.X.; Deng, L.H.; Chen, W.W.; Shi, N.; Jin, T.; Lin, Z.Q.; Ma, Y.; Jiang, K.; Yang, X.N.; Xia, Q. Circulating microRNA 216 as a marker for the early identification of severe acute pancreatitis. Am. J. Med. Sci., 2017, 353(2), 178-186.
[http://dx.doi.org/10.1016/j.amjms.2016.12.007] [PMID: 28183420]
[16]
Li, X.; Lin, Z.; Wang, L.; Liu, Q.; Cao, Z.; Huang, Z.; Zhong, M.; Peng, S.; Zhang, Y.; Li, Y.; Ma, X. RNA-Seq analyses of the role of miR-21 in acute pancreatitis. Cell. Physiol. Biochem., 2018, 51(5), 2198-2211.
[17]
Blenkiron, C.; Askelund, K.J.; Shanbhag, S.T.; Chakraborty, M.; Petrov, M.S.; Delahunt, B.; Windsor, J.A.; Phillips, A.R. MicroRNAs in mesenteric lymph and plasma during acute pancreatitis. Ann. Surg., 2014, 260(2), 341-347.
[http://dx.doi.org/10.1097/SLA.0000000000000447] [PMID: 24509209]
[18]
Wang, J.; Huang, W.; Thibault, S.; Brown, T.P.; Bobrowski, W.; Gukasyan, H.J.; Evering, W.; Hu, W.; John-Baptiste, A.; Vitsky, A. Evaluation of miR-216a and miR-217 as potential biomarkers of acute exocrine pancreatic toxicity in rats. Toxicol. Pathol., 2017, 45(2), 321-334.
[http://dx.doi.org/10.1177/0192623316678090] [PMID: 28013573]
[19]
Lee, H.B.; Park, H.K.; Choi, H.J.; Lee, S.; Lee, S.J.; Lee, J.Y.; Cho, E.H.; Han, H.J.; Seok, J.H.; Son, W.C. Evaluation of circulating MicroRNA biomarkers in the acute pancreatic injury dog model. Int. J. Mol. Sci., 2018, 19(10), 3048.
[http://dx.doi.org/10.3390/ijms19103048] [PMID: 30301227]
[20]
Rouse, R.; Rosenzweig, B.; Shea, K.; Knapton, A.; Stewart, S.; Xu, L.; Chockalingam, A.; Zadrozny, L.; Thompson, K. MicroRNA biomarkers of pancreatic injury in a canine model. Exp. Toxicol. Pathol., 2017, 69(1), 33-43.
[21]
Dixit, A.K.; Sarver, A.E.; Yuan, Z.; George, J.; Barlass, U.; Cheema, H.; Sareen, A.; Banerjee, S.; Dudeja, V.; Dawra, R.; Subramanian, S.; Saluja, A.K. Comprehensive analysis of microRNA signature of mouse pancreatic acini: Overexpression of miR-21-3p in acute pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol., 2016, 311(5), G974-G980.
[http://dx.doi.org/10.1152/ajpgi.00191.2016] [PMID: 27686613]
[22]
Lu, P.; Wang, F.; Wu, J.; Wang, C.; Yan, J.; Li, Z.; Song, J.; Wang, J. Elevated Serum miR-7, miR-9, miR-122, and miR-141 are noninvasive biomarkers of acute pancreatitis. Dis. Markers, 2017, 2017, 1-8.
[http://dx.doi.org/10.1155/2017/7293459] [PMID: 29332987]
[23]
Zhang, J.; Ning, X.; Cui, W.; Bi, M.; Zhang, D.; Zhang, J. Transforming growth factor (TGF)-β-induced microRNA-216a promotes acute pancreatitis via Akt and TGF-β pathway in mice. Dig. Dis. Sci., 2015, 60(1), 127-135.
[http://dx.doi.org/10.1007/s10620-014-3261-9] [PMID: 25501921]
[24]
Wu, X.; Chen, W.; Cai, H.; Hu, J.; Wu, B.; Jiang, Y.; Chen, X.; Sun, D.; An, Y. MiR-216b inhibits pancreatic cancer cell progression and promotes apoptosis by down-regulating KRAS. Arch. Med. Sci., 2018, 14(6), 1321-1332.
[http://dx.doi.org/10.5114/aoms.2018.72564] [PMID: 30393486]
[25]
You, Y.; Tan, J.; Gong, Y.; Dai, H.; Chen, H.; Xu, X.; Yang, A.; Zhang, Y.; Bie, P. MicroRNA-216b-5p functions as a tumor-suppressive RNA by targeting TPT1 in pancreatic cancer cells. J. Cancer, 2017, 8(14), 2854-2865.
[http://dx.doi.org/10.7150/jca.18931] [PMID: 28928875]
[26]
Zhao, W.G.; Yu, S.N.; Lu, Z.H.; Ma, Y.H.; Gu, Y.M.; Chen, J. The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. Carcinogenesis, 2010, 31(10), 1726-1733.
[http://dx.doi.org/10.1093/carcin/bgq160] [PMID: 20675343]
[27]
Goodwin, D.; Rosenzweig, B.; Zhang, J.; Xu, L.; Stewart, S.; Thompson, K.; Rouse, R. Evaluation of miR-216a and miR-217 as potential biomarkers of acute pancreatic injury in rats and mice. Biomarkers, 2014, 19(6), 517-529.
[28]
Calvano, J.; Edwards, G.; Hixson, C.; Burr, H.; Mangipudy, R.; Tirmenstein, M. Serum microRNAs-217 and -375 as biomarkers of acute pancreatic injury in rats. Toxicology, 2016, 368-369, 1-9.
[http://dx.doi.org/10.1016/j.tox.2016.08.009] [PMID: 27521901]
[29]
Eliasson, L. The small RNA miR-375-a pancreatic islet abundant miRNA with multiple roles in endocrine beta cell function. Mol. Cell. Endocrinol., 2017, 456, 95-101.
[http://dx.doi.org/10.1016/j.mce.2017.02.043] [PMID: 28254488]
[30]
Zhao, S.P.; Yu, C.; Xiang, K.M.; Yang, M.S.; Liu, Z.L.; Yang, B.C. miR-375 inhibits autophagy and further promotes inflammation and apoptosis of acinar cells by targeting ATG7. Pancreas, 2020, 49(4), 543-551.
[http://dx.doi.org/10.1097/MPA.0000000000001536] [PMID: 32282768]
[31]
Yu, W.; Zhang, M.; Li, X.; Pan, N.; Bian, X.; Wu, W. Protective effect of miR-193a-5p and miR-320-5p on caerulein-induced injury in AR42J cells. Dig. Dis. Sci., 2021, 66(12), 4333-4343.
[http://dx.doi.org/10.1007/s10620-020-06800-7] [PMID: 33405047]
[32]
Zhen, J.; Chen, W.; Liu, Y.; Zang, X. Baicalin protects against acute pancreatitis involving JNK signaling pathway via regulating miR-15a. Am. J. Chin. Med., 2021, 49(1), 147-161.
[http://dx.doi.org/10.1142/S0192415X21500087] [PMID: 33371810]

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