Clinical and biological significance of circulating miRNAs in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation.
biomarkers
chronic pancreatitis
circulating miRNAs
islet autotransplantation
Journal
Clinical and translational medicine
ISSN: 2001-1326
Titre abrégé: Clin Transl Med
Pays: United States
ID NLM: 101597971
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
12
09
2023
received:
27
03
2023
accepted:
30
09
2023
medline:
23
10
2023
pubmed:
17
10
2023
entrez:
17
10
2023
Statut:
ppublish
Résumé
Specific microRNAs (miRNAs) were elevated in chronic pancreatitis (CP) patients during islet infusion after total pancreatectomy (TPIAT). We aimed to identify circulating miRNA signatures of pancreatic damage, predict miRNA-mRNA networks to identify potential links to CP pathogenesis and identify islet isolation and transplantation functional outcomes. Small RNA sequencing was performed to identify distinct circulating miRNA signatures in CP. Plasma miRNAs were measured using miRCURY LNA SYBR green quantitative real-time polymerase chain reaction assays. Correlation analyses were performed using R software. The miRNA target and disease interactions were determined using miRNet and the miRNA enrichment and annotation tool. Alterations were found in circulating miRNAs in CP patients compared to healthy controls. Further studies were conducted on 12 circulating miRNAs enriched in the pancreas, other tissues and other diseases including cancer and fibrosis. Approximately 2888 mRNAs in the pancreas were their targets, demonstrating interactions with 76 small molecules. Three miRNAs exhibited interactions with morphine and five exhibited interactions with glucose. The miRNA panel targeted 22 genes associated with pancreatitis. The islet-specific, acinar cell-specific and liver-specific miRNAs were elevated at 6 h after islet infusion and returned to baseline levels 3 months after TPIAT. Circulating levels of miRNAs returned to pre-transplant levels 1-year post-transplant. Circulating miRNAs measured before and 6 h after islet infusion were directly or inversely associated with metabolic outcomes at 3 and 6 months post-transplant. miRNAs may contribute to CP pathogenesis, and elevated circulating levels may be specific to pancreatic inflammation and fibrosis, warranting further investigation.
Sections du résumé
BACKGROUND
Specific microRNAs (miRNAs) were elevated in chronic pancreatitis (CP) patients during islet infusion after total pancreatectomy (TPIAT). We aimed to identify circulating miRNA signatures of pancreatic damage, predict miRNA-mRNA networks to identify potential links to CP pathogenesis and identify islet isolation and transplantation functional outcomes.
METHODS
Small RNA sequencing was performed to identify distinct circulating miRNA signatures in CP. Plasma miRNAs were measured using miRCURY LNA SYBR green quantitative real-time polymerase chain reaction assays. Correlation analyses were performed using R software. The miRNA target and disease interactions were determined using miRNet and the miRNA enrichment and annotation tool.
RESULTS
Alterations were found in circulating miRNAs in CP patients compared to healthy controls. Further studies were conducted on 12 circulating miRNAs enriched in the pancreas, other tissues and other diseases including cancer and fibrosis. Approximately 2888 mRNAs in the pancreas were their targets, demonstrating interactions with 76 small molecules. Three miRNAs exhibited interactions with morphine and five exhibited interactions with glucose. The miRNA panel targeted 22 genes associated with pancreatitis. The islet-specific, acinar cell-specific and liver-specific miRNAs were elevated at 6 h after islet infusion and returned to baseline levels 3 months after TPIAT. Circulating levels of miRNAs returned to pre-transplant levels 1-year post-transplant. Circulating miRNAs measured before and 6 h after islet infusion were directly or inversely associated with metabolic outcomes at 3 and 6 months post-transplant.
CONCLUSIONS
miRNAs may contribute to CP pathogenesis, and elevated circulating levels may be specific to pancreatic inflammation and fibrosis, warranting further investigation.
Identifiants
pubmed: 37846205
doi: 10.1002/ctm2.1434
pmc: PMC10579997
doi:
Substances chimiques
Circulating MicroRNA
0
MicroRNAs
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1434Informations de copyright
© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
Références
Finn SMB, Bellin MD. Total pancreatectomy with islet autotransplantation: new insights on the pathology and pathogenesis of chronic pancreatitis from tissue research. Surg Pathol Clin. 2022;15(3):503-509. doi:10.1016/j.path.2022.05.005
Bellin MD, Kerdsirichairat T, Beilman GJ, et al. Total pancreatectomy with islet autotransplantation improves quality of life in patients with refractory recurrent acute pancreatitis. Clin Gastroenterol Hepatol. 2016;14(9):1317-1323. doi:10.1016/j.cgh.2016.02.027
Uc A, Andersen DK, Bellin MD, et al. Chronic pancreatitis in the 21st century-research challenges and opportunities: summary of a National Institute of Diabetes and Digestive and Kidney Diseases workshop. Pancreas. 2016;45(10):1365-1375. doi:10.1097/mpa.0000000000000713
Abu-El-Haija M, Anazawa T, Beilman GJ, et al. The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: a report from the International Consensus Guidelines in chronic pancreatitis. Pancreatology. 2020;20(4):762-771. doi:10.1016/j.pan.2020.04.005
Bellin MD, Abu-El-Haija M, Morgan K, et al. A multicenter study of total pancreatectomy with islet autotransplantation (TPIAT): POST (Prospective Observational Study of TPIAT). Pancreatology. 2018;18(3):286-290. doi:10.1016/j.pan.2018.02.001
Vasu S, Yang JM, Hodges J, et al. Circulating miRNA in patients undergoing total pancreatectomy and islet autotransplantation. Cell Transplant. 2021;30:963689721999330. doi:10.1177/0963689721999330
Chinnakotla S, Beilman GJ, Dunn TB, et al. Factors predicting outcomes after a total pancreatectomy and islet autotransplantation lessons learned from over 500 cases. Ann Surg. 2015;262(4):610-622. doi:10.1097/sla.0000000000001453
Kanak MA, Takita M, Shahbazov R, et al. Evaluation of microRNA375 as a novel biomarker for graft damage in clinical islet transplantation. Transplantation. 2015;99(8):1568-1573. doi:10.1097/tp.0000000000000625
Saravanan PB, Kanak MA, Chang CA, et al. Islet damage during isolation as assessed by miRNAs and the correlation of miRNA levels with posttransplantation outcome in islet autotransplantation. Am J Transplant. 2018;18(4):982-989. doi:10.1111/ajt.14615
Saravanan PB, Vasu S, Yoshimatsu G, et al. Differential expression and release of exosomal miRNAs by human islets under inflammatory and hypoxic stress. Diabetologia. 2019;62(10):1901-1914. doi:10.1007/s00125-019-4950-x
Yoshimatsu G, Takita M, Kanak MA, et al. MiR-375 and miR-200c as predictive biomarkers of islet isolation and transplantation in total pancreatectomy with islet autotransplantation. J Hepatobiliary Pancreat Sci. 2016;23(9):585-594. doi:10.1002/jhbp.377
Chhatriya B, Sarkar P, Nath D, et al. Pilot study identifying circulating miRNA signature specific to alcoholic chronic pancreatitis and its implication on alcohol-mediated pancreatic tissue injury. JGH Open. 2020;4(6):1079-1087. doi:10.1002/jgh3.12389
Lu P, Wang F, Wu J, et al. Elevated serum miR-7, miR-9, miR-122, and miR-141 are noninvasive biomarkers of acute pancreatitis. Dis Markers. 2017;2017:7293459. doi:10.1155/2017/7293459
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(1). doi:10.3390/cancers12010197
Xin L, Gao J, Wang D, et al. Novel blood-based microRNA biomarker panel for early diagnosis of chronic pancreatitis. Sci Rep. 2017;7:40019. doi:10.1038/srep40019
Jia YC, Ding YX, Mei WT, et al. Extracellular vesicles and pancreatitis: mechanisms, status and perspectives. Int J Biol Sci. 2021;17(2):549-561. doi:10.7150/ijbs.54858
Masamune A, Nakano E, Hamada S, Takikawa T, Yoshida N, Shimosegawa T. Alteration of the microRNA expression profile during the activation of pancreatic stellate cells. Scand J Gastroenterol. 2014;49(3):323-331. doi:10.3109/00365521.2013.876447
Wang D, Xin L, Lin JH, et al. Identifying miRNA-mRNA regulation network of chronic pancreatitis based on the significant functional expression. Medicine (Baltimore). 2017;96(21):e6668. doi:10.1097/md.0000000000006668
Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. next generation sequencing; small RNA; microRNA; adapter removal. EMBnet J. 2011;17(1):3. doi:10.14806/ej.17.1.200 2011-05-02 2011
Friedlander MR, Mackowiak SD, Li N, Chen W, Rajewsky N. miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades. Nucleic Acids Res. 2012;40(1):37-52. doi:10.1093/nar/gkr688
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi:10.1186/s13059-014-0550-8
Team RC, The R Project for Statistical Computing. The R Foundation. Accessed January 2021. https://www.r-project.org
Kern F, Fehlmann T, Solomon J, et al. miEAA 2.0: integrating multi-species microRNA enrichment analysis and workflow management systems. Nucleic Acids Res. 2020;48(W1):W521-w528. doi:10.1093/nar/gkaa309
Chang L, Zhou G, Soufan O, Xia J. miRNet 2.0: network-based visual analytics for miRNA functional analysis and systems biology. Nucleic Acids Res. 2020;48(W1):W244-w251. doi:10.1093/nar/gkaa467
Agarwal V, Bell GW, Nam JW, Bartel DP, Predicting effective microRNA target sites in mammalian mRNAs. Elife. Aug 12 2015;4 doi:10.7554/eLife.05005
Team M, Compare lists-multiple list comparator. Molbiotools. Accessed February, 2022. https://molbiotools.com/listcompare.php
Team TBC, Bioconductor: open source software for bioinformatics. Bioconductor. Accessed August 2021, 2021. https://bioconductor.org
Erdos Z, Barnum JE, Wang E, et al. Evaluation of the relative performance of pancreas-specific microRNAs in rat plasma as biomarkers of pancreas injury. Toxicol Sci. 2020;173(1):5-18. doi:10.1093/toxsci/kfz184
Zhou X, Lu Z, Wang T, Huang Z, Zhu W, Miao Y. Plasma miRNAs in diagnosis and prognosis of pancreatic cancer: a miRNA expression analysis. Gene. 2018;673:181-193. doi:10.1016/j.gene.2018.06.037
Mattke J, Vasu S, Darden CM, Kumano K, Lawrence MC, Naziruddin B. Role of exosomes in islet transplantation. Front Endocrinol (Lausanne). 2021;12:681600. doi:10.3389/fendo.2021.681600
Su Y, Buchler P, Gazdhar A, et al. Pancreatic regeneration in chronic pancreatitis requires activation of the notch signaling pathway. J Gastrointest Surg. 2006;10(9):1230-1241. doi:10.1016/j.gassur.2006.08.017. discussion 1242.
Gasiorowska A, Talar-Wojnarowska R, Kaczka A, Borkowska A, Czupryniak L, Malecka-Panas E. Subclinical inflammation and endothelial dysfunction in patients with chronic pancreatitis and newly diagnosed pancreatic cancer. Dig Dis Sci. 2016;61(4):1121-1129. doi:10.1007/s10620-015-3972-6
Qu J, Chen X, Sun YZ, Li JQ, Ming Z. Inferring potential small molecule-miRNA association based on triple layer heterogeneous network. J Cheminform. 2018;10(1):30. doi:10.1186/s13321-018-0284-9
Toyama K, Kiyosawa N, Watanabe K, Ishizuka H. Identification of circulating miRNAs differentially regulated by opioid treatment. Int J Mol Sci. 2017;18(9). doi:10.3390/ijms18091991
He Y, Yang C, Kirkmire CM, Wang ZJ. Regulation of opioid tolerance by let-7 family microRNA targeting the mu opioid receptor. J Neurosci. 2010;30(30):10251-10258. doi:10.1523/jneurosci.2419-10.2010
Vasu S, Kumano K, Darden CM, Rahman I, Lawrence MC, Naziruddin B. MicroRNA signatures as future biomarkers for diagnosis of diabetes states. Cells. 2019;8(12). doi:10.3390/cells8121533
Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207-210. doi:10.1093/nar/30.1.207
Vasu SLM, Naziruddin B, Data from: Circulating miRNAs in Chronic Pancreatitis. 2023.