Differential expressions of miR-223, miR-424, miR-145, miR-200c, miR-139 in experimental rat chronic pancreatitis model and their relationship between oxidative stress, endoplasmic reticulum stress, and apoptosis

Document Type : Original Article


1 University of Health Sciences Turkey, Institution of Medical Sciences, Department of Molecular Biology and Genetics, Istanbul, Turkey

2 University of Health Sciences Turkey, Experimental Medicine Research and Application Center, Uskudar, 34662, Istanbul, Turkey


Objective(s): This study aimed to research the roles of miR-139, miR-221, miR-200c, miR-145, miR-223, miR-424, and miR-377 in endoplasmic reticulum stress (ERS), oxidative stress (OS), fibrosis, and apoptosis processes in chronic pancreatitis (CP) rat model.
Materials and Methods: Fourteen rats were randomized into 2 groups (Group 1, sham group (n=7) and Group 2, CP group (n=7)). TGF-beta and malondialdehyde concentrations were measured in rat blood samples. qRT-PCR was used to investigate the expression levels of 7 miRNAs in the pancreas tissues. The correlations of mRNA undergoing significant changes with inflammation (TNF-α, IL-6), ERS (Ire1-α, Perk), apoptosis (Caspase 3, Bcl-2), OS (Cat, Gpx1), and fibrosis (α-Sma) were investigated.
Results: The biochemical results and histopathological scores in Group 1 were statistically significantly high compared with Group 2 (p <0.5). Expression levels of seven miRNAs (miR-200c, miR-145, miR-223, miR-424) were significantly higher, while miR-139 was significantly lower in CP. In our study, we found that miR-200c, miR-145, and miR-139 may contribute to CP progression and cellular processes based on the correlation between ERS, OS, apoptosis, and inflammation with miRNA expression levels.
Conclusion: miR-200c, miR-145, miR-139, miR-223, and miR-424 play roles in the CP model. They may be used as candidate biomarkers for the CP process.


1. Machicado JD, Amann ST, Anderson MA, Abberbock J, Sherman S, Conwell DL, et al. Quality of life in chronic pancreatitis is determined by constant pain, disability/unemployment, current smoking, and associated co-morbidities. Am J Gastroenterol 2017; 112:633-642.
2. Guzel Tanoglu E, Tanoğlu A, Aydin Meriçöz M, Esen MF. Melatonin has favorable preventive effects on experimental chronic pancreatitis rat model. Turk J Med Sci 2021.
3. Yildirim M, Kaplan M, Duzenli T, Tanoglu A, Kucukodaci Z, Onal Tastan Y, et al. Pentoxifylline has favorable preventive effects on experimental chronic pancreatitis model. Scand J Gastroenterol 2020; 55:236-241.
4. Yalçınkaya B, Güzel E, Taştekin D, Pençe S. Role of mir-33a, mir-203b, mir361-3p, and mir-424 in hepatocellular carcinoma. Turk J Med Sci 2021; 51:638-643.
5. Demirel G, Guzel E, Creighton CJ, Ozturk YE, Kucuk C, Asliyuksek H, et al. MDMA abuse in relation to microrna variation in human brain ventral tegmental area and nucleus accumbens. Iran J Pharm Res 2019; 18:1989-1999.
6. Xin L, Gao J, Wang D, Lin JH, Liao Z, Ji JT, et al. Novel blood-based microRNA biomarker panel for early diagnosis of chronic pancreatitis. Sci Rep 2017; 7:40019.
7. Guzel E, Karatas OF, Semercioz A, Ekici S, Aykan S, Yentur S, et al. Identification of microRNAs differentially expressed in prostatic secretions of patients with prostate cancer. Int J Cancer 2015; 136:875-879.
8. Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 2003; 113:25-36.
9. Hu LH, Ji JT, Li ZS. Potential application of miRNAs as diagnostic and therapeutic tools in chronic pancreatitis. J Cell Mol Med 2015; 19:2049-2057.
10. Verlaan M, Roelofs HM, van-Schaik A, Wanten GJ, Jansen JB, Peters WH, et al. Assessment of oxidative stress in chronic pancreatitis patients. World J Gastroenterol 2006; 12:5705-5710.
11. Sah RP, Garg SK, Dixit AK, Dudeja V, Dawra RK, Saluja AK. Endoplasmic reticulum stress is chronically activated in chronic pancreatitis. J Biol Chem 2014; 289:27551-27561.
12. Nathan JD, Romac J, Peng RY, Peyton M, Rockey DC, Liddle RA. Protection against chronic pancreatitis and pancreatic fibrosis in mice overexpressing pancreatic secretory trypsin inhibitor. Pancreas 2010; 39:e24-30.
13. Banks PA, Conwell DL, Toskes PP. The management of acute and chronic pancreatitis. Gastroenterol Hepatol (N Y) 2010; 6:1-16.
14. Guo Y, Fan W, Cao S, Xie Y, Hong J, Zhou H, et al. 2,3,5,4’-Tetrahydroxystilbene-2-O-β-D-Glucoside modulated human umbilical vein endothelial cells injury under oxidative stress. Korean J Physiol Pharmacol 2020; 24:473-479.
15. Xue M, Peng N, Zhu X, Zhang H. Hsa_circ_0006872 promotes cigarette smoke-induced apoptosis, inflammation and oxidative stress in HPMECs and BEAS-2B cells through the miR-145-5p/NF-κB axis. Biochem Biophys Res Commun 2021; 534:553-560.
16. Pajic M, Froio D, Daly S, Doculara L, Millar E, Graham PH, et al. miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ros defense. Cancer Res 2018; 78:501-515.
17. Wei H, Huang L, Wei F, Li G, Huang B, Li J, et al. Up-regulation of miR-139-5p protects diabetic mice from liver tissue damage and oxidative stress through inhibiting Notch signaling pathway. Acta Biochim Biophys Sin (Shanghai) 2020; 52:390-400.
18. Li T, Liang S, Zhang Y, Chen Y. Effects of microRNA-139 on myocardial cell injury induced by oxidative stress. Int J Clin Exp Med 2015; 8:19994-20001.
19. Deng B, Wang M, Liu Z. A panel of 8 miRNAs as a novel diagnostic biomarker in pancreatic cancer. Medicine (Baltimore) 2020; 99:e22261.
20. Gomez JL, Chen A, Diaz MP, Zirn N, Gupta A, Britto C, et al. A network of sputum MicroRNAs ıs associated with neutrophilic airway ınflammation in asthma. Am J Respir Crit Care Med 2020; 202:51-64.
21. Wang WX, Prajapati P, Nelson PT, Springer JE. The mitochondria-associated er membranes are novel subcellular locations enriched for ınflammatory-responsive microRNAs. Mol Neurobiol 2020; 57:2996-3013.
22. Zhu J, Lv J, Chen J, Zhang X, Ji Y. Down-regulated microRNA-223 or elevated ZIC1 inhibits the development of pancreatic cancer via inhibiting PI3K/Akt/mTOR signaling pathway activation. Cell Cycle 2020; 19:2851-2865.
23. Zhang S, Cai X, Huang F, Zhong W, Yu Z. Effect of trichostatin a on viability and microRNA expression in human pancreatic cancer cell line BxPC-3. Exp Oncol 2008; 30:265-268.
24. Lin Y, Ge X, Wen Y, Shi ZM, Chen QD, Wang M, et al. MiRNA-145 increases therapeutic sensibility to gemcitabine treatment of pancreatic adenocarcinoma cells. Oncotarget 2016; 7:70857-70868.
25. Zhou H, Zhang L, Tu H. Downregulation of thymopoietin by miR-139-5p suppresses cell proliferation and induces cell cycle arrest/apoptosis in pancreatic ductal adenocarcinoma. Oncol Lett 2019; 18:3443-3452.
26. Wu K, Hu G, He X, Zhou P, Li J, He B, et al. MicroRNA-424-5p suppresses the expression of SOCS6 in pancreatic cancer. Pathol Oncol Res 2013; 19:739-748.
27. Ren Z, Wang X, Xu M, Yang F, Frank JA, Ke ZJ, et al. Binge ethanol exposure causes endoplasmic reticulum stress, oxidative stress and tissue injury in the pancreas. Oncotarget 2016; 7:54303-54316.
28. Bhardwaj P, Yadav RK. Chronic pancreatitis: role of oxidative stress and anti-oxidants. Free Radic Res 2013; 47:941-949.
29. Reese M, Flammang I, Yang Z, Dhayat SA. Potential of exosomal microrna-200b as liquid biopsy marker in pancreatic ductal adenocarcinoma. Cancers (Basel) 2020; 12:197.
30. Wang D, Xin L, Lin JH, Liao Z, Ji JT, Du TT, et al. Identifying miRNA-mRNA regulation network of chronic pancreatitis based on the significant functional expression. Medicine (Baltimore) 2017; 96:e6668.