{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:34Z","timestamp":1787027854593,"version":"build-2736575974"},"reference-count":104,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T00:00:00Z","timestamp":1700006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK124342"],"award-info":[{"award-number":["DK124342"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Kr\u00fcppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion of Klf5 and the activation of KrasG12D mutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control and KrasG12D mutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata with Klf5 loss (with or without KrasG12D) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion of Klf5 reduced the expression level of cytokines and fibrotic components such as Il1b, Il6, Tnf, Tgfb1, Timp1, and Mmp9. Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters of Il1b, Il6, and Tgfb1 genes. In summary, the inactivation of Klf5 inhibits ADM and PanIN formation and the development of pancreatic fibrosis.<\/jats:p>","DOI":"10.3390\/cancers15225427","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T10:57:46Z","timestamp":1700045866000},"page":"5427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Kr\u00fcppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis"],"prefix":"10.3390","volume":"15","author":[{"given":"Maryam","family":"Alavi","sequence":"first","affiliation":[{"name":"Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4266-6444","authenticated-orcid":false,"given":"Ana","family":"Mejia-Bautista","sequence":"additional","affiliation":[{"name":"Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyi","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jela","family":"Bandovic","sequence":"additional","affiliation":[{"name":"Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avi Z.","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University, Baltimore, MD 21217, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2127-7714","authenticated-orcid":false,"given":"Agnieszka B.","family":"Bialkowska","sequence":"additional","affiliation":[{"name":"Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1053\/j.gastro.2015.08.045","article-title":"Burden of Gastrointestinal, Liver, and Pancreatic Diseases in the United States","volume":"149","author":"Peery","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_2","unstructured":"Gapp, J., and Chandra, S. (2022). Acute Pancreatitis, StatPearls."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1056\/NEJMra1505202","article-title":"Acute Pancreatitis","volume":"375","author":"Forsmark","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.path.2016.05.008","article-title":"Chronic Pancreatitis","volume":"9","author":"Stram","year":"2016","journal-title":"Surg. Pathol. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1755-1536-4-26","article-title":"Animal models for investigating chronic pancreatitis","volume":"4","author":"Aghdassi","year":"2011","journal-title":"Fibrogenesis Tissue Repair"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1007\/s12026-014-8504-5","article-title":"Immune cells and immune-based therapy in pancreatitis","volume":"58","author":"Xue","year":"2014","journal-title":"Immunol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1097\/MOG.0000000000000387","article-title":"Immunology of pancreatitis and environmental factors","volume":"33","author":"Lee","year":"2017","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jcmgh.2017.05.005","article-title":"Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS(G12D)-driven Pancreatic Tumorigenesis","volume":"4","author":"Chuvin","year":"2017","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/978-1-4939-8879-2_26","article-title":"Pancreatic Acinar-to-Ductal Metaplasia and Pancreatic Cancer","volume":"1882","author":"Wang","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Johnson, B.L., d\u2019Alincourt Salazar, M., Mackenzie-Dyck, S., D\u2019Apuzzo, M., Shih, H.P., Manuel, E.R., and Diamond, D.J. (2019). Desmoplasia and oncogene driven acinar-to-ductal metaplasia are concurrent events during acinar cell-derived pancreatic cancer initiation in young adult mice. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0221810"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"344","DOI":"10.3389\/fphys.2012.00344","article-title":"Pancreatic stellate cells: A starring role in normal and diseased pancreas","volume":"3","author":"Apte","year":"2012","journal-title":"Front. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S48","DOI":"10.1016\/j.cgh.2009.07.038","article-title":"Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis","volume":"7","author":"Masamune","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1016\/S0002-9440(10)61125-X","article-title":"Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis","volume":"160","author":"Shek","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1136\/gut.52.5.677","article-title":"Cell migration: A novel aspect of pancreatic stellate cell biology","volume":"52","author":"Phillips","year":"2003","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1172\/JCI30082","article-title":"The pancreatic stellate cell: A star on the rise in pancreatic diseases","volume":"117","author":"Omary","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1136\/gut.44.4.534","article-title":"Pancreatic stellate cells are activated by proinflammatory cytokines: Implications for pancreatic fibrogenesis","volume":"44","author":"Apte","year":"1999","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1177\/145749690509400205","article-title":"Fibrogenesis in the pancreas after acinar cell injury","volume":"94","author":"Patel","year":"2005","journal-title":"Scand. J. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1097\/00006676-200311000-00008","article-title":"Stellate cell activation in alcoholic pancreatitis","volume":"27","author":"Apte","year":"2003","journal-title":"Pancreas"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3748\/wjg.v23.i3.382","article-title":"Pancreatic stellate cell: Pandora\u2019s box for pancreatic disease biology","volume":"23","author":"Bynigeri","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_20","first-page":"99","article-title":"Pathology and pathogenesis of diseases of the pancreas","volume":"107","author":"Longnecker","year":"1982","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cicenas, J., Kvederaviciute, K., Meskinyte, I., Meskinyte-Kausiliene, E., Skeberdyte, A., and Cicenas, J. (2017). KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer. Cancers, 9.","DOI":"10.3390\/cancers9050042"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18907","DOI":"10.1073\/pnas.0810111105","article-title":"Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia","volume":"105","author":"Emerson","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18913","DOI":"10.1073\/pnas.0810097105","article-title":"Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice","volume":"105","author":"Habbe","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1056\/NEJMra0901557","article-title":"Pancreatic cancer","volume":"362","author":"Hidalgo","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4846","DOI":"10.3748\/wjg.v24.i43.4846","article-title":"Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes","volume":"24","author":"McGuigan","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S40","DOI":"10.1016\/j.cgh.2009.07.040","article-title":"Ras activity in acinar cells links chronic pancreatitis and pancreatic cancer","volume":"7","author":"Logsdon","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/MPA.0000000000000975","article-title":"Progression of Chronic Pancreatitis to Pancreatic Cancer: Is There a Role of Gene Mutations as a Screening Tool?","volume":"47","author":"Rashid","year":"2018","journal-title":"Pancreas"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1172\/JCI59743","article-title":"An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice","volume":"122","author":"Daniluk","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ccr.2007.01.012","article-title":"Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice","volume":"11","author":"Guerra","year":"2007","journal-title":"Cancer Cell."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.bbrc.2009.03.068","article-title":"Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras","volume":"382","author":"Carriere","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1172\/JCI40045","article-title":"Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice","volume":"120","author":"Morris","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1152\/physrev.00058.2009","article-title":"Mammalian Kruppel-like factors in health and diseases","volume":"90","author":"McConnell","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6897","DOI":"10.1074\/jbc.C000870200","article-title":"Intestinal-enriched Kruppel-like factor (Kruppel-like factor 5) is a positive regulator of cellular proliferation","volume":"276","author":"Sun","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2004.11.005","article-title":"Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation","volume":"1","author":"Oishi","year":"2005","journal-title":"Cell. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"G1784","DOI":"10.1152\/ajpgi.00541.2006","article-title":"Overexpression of Kruppel-like factor 5 in esophageal epithelia in vivo leads to increased proliferation in basal but not suprabasal cells","volume":"292","author":"Goldstein","year":"2007","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4125","DOI":"10.1158\/0008-5472.CAN-08-4402","article-title":"Haploinsufficiency of Kruppel-like factor 5 rescues the tumor-initiating effect of the Apc(Min) mutation in the intestine","volume":"69","author":"McConnell","year":"2009","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e153488","DOI":"10.1172\/jci.insight.153488","article-title":"KLF5 protects the intestinal epithelium against Th17 immune response in a murine colitis model","volume":"7","author":"Shieh","year":"2022","journal-title":"JCI Insight"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.jcmgh.2019.11.009","article-title":"Kruppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells","volume":"9","author":"Kim","year":"2020","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"G478","DOI":"10.1152\/ajpgi.00172.2017","article-title":"Kruppel-like factor 5 is essential for maintenance of barrier function in mouse colon","volume":"313","author":"Liu","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1053\/j.gastro.2017.03.035","article-title":"SP and KLF Transcription Factors in Digestive Physiology and Diseases","volume":"152","author":"Kim","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1038\/sj.onc.1207397","article-title":"Kruppel-like factor 5 mediates the transforming activity of oncogenic H-Ras","volume":"23","author":"Nandan","year":"2004","journal-title":"Oncogene"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12300","DOI":"10.1074\/jbc.M305025200","article-title":"Blood lipid mediator sphingosine 1-phosphate potently stimulates platelet-derived growth factor-A and -B chain expression through S1P1-Gi-Ras-MAPK-dependent induction of Kruppel-like factor 5","volume":"279","author":"Usui","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1093\/nar\/gkl014","article-title":"Kruppel-like factor 5 is an important mediator for lipopolysaccharide-induced proinflammatory response in intestinal epithelial cells","volume":"34","author":"Chanchevalap","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1096\/fj.06-6694com","article-title":"Kruppel-like factor 5 activates MEK\/ERK signaling via EGFR in primary squamous epithelial cells","volume":"21","author":"Yang","year":"2007","journal-title":"FASEB J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1053\/j.gastro.2007.10.023","article-title":"Kruppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis","volume":"134","author":"Nandan","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5997","DOI":"10.1074\/jbc.M113.508549","article-title":"A colon cancer-derived mutant of Kruppel-like factor 5 (KLF5) is resistant to degradation by glycogen synthase kinase 3beta (GSK3beta) and the E3 ubiquitin ligase F-box and WD repeat domain-containing 7alpha (FBW7alpha)","volume":"289","author":"Bialkowska","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nrc3582","article-title":"Kruppel-like factors in cancer","volume":"13","author":"Tetreault","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5079","DOI":"10.1038\/sj.onc.1208696","article-title":"Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes","volume":"24","author":"Grutzmann","year":"2005","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Shain, A.H., Salari, K., Giacomini, C.P., and Pollack, J.R. (2013). Integrative genomic and functional profiling of the pancreatic cancer genome. BMC Genom., 14.","DOI":"10.1186\/1471-2164-14-624"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eaan2507","DOI":"10.1126\/science.aan2507","article-title":"A pathology atlas of the human cancer transcriptome","volume":"357","author":"Uhlen","year":"2017","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1053\/j.gastro.2017.12.005","article-title":"Kruppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice","volume":"154","author":"He","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Bai, H., Chen, X., Zhang, L., and Dou, X. (2012). The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates inflammation and fibrosis in a mouse model of chronic pancreatitis. BMC Gastroenterol., 12.","DOI":"10.1186\/1471-230X-12-115"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"G1105","DOI":"10.1152\/ajpgi.00431.2001","article-title":"Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis","volume":"282","author":"Demols","year":"2002","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"D165","DOI":"10.1093\/nar\/gkab1113","article-title":"JASPAR 2022: The 9th release of the open-access database of transcription factor binding profiles","volume":"50","author":"Rauluseviciute","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3389\/fncel.2019.00095","article-title":"TF-ChIP Method for Tissue-Specific Gene Targets","volume":"13","author":"Perna","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/embj.201592404","article-title":"Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer","volume":"35","author":"Diaferia","year":"2016","journal-title":"EMBO J."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Winter, K., Dzieniecka, M., Strzelczyk, J., Wagrowska-Danilewicz, M., Danilewicz, M., and Malecka-Wojciesko, E. (2021). Alpha Smooth Muscle Actin (alphaSMA) Immunohistochemistry Use in the Differentiation of Pancreatic Cancer from Chronic Pancreatitis. J. Clin. Med., 10.","DOI":"10.3390\/jcm10245804"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Van De Vlekkert, D., Machado, E., and d\u2019Azzo, A. (2020). Analysis of Generalized Fibrosis in Mouse Tissue Sections with Masson\u2019s Trichrome Staining. Bio-Protocol, 10.","DOI":"10.21769\/BioProtoc.3629"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.mex.2015.02.007","article-title":"Determination of collagen content within picrosirius red stained paraffin-embedded tissue sections using fluorescence microscopy","volume":"2","author":"Vogel","year":"2015","journal-title":"MethodsX"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5778","DOI":"10.1096\/fj.201800241RR","article-title":"Genetically induced vs. classical animal models of chronic pancreatitis: A critical comparison","volume":"32","author":"Klauss","year":"2018","journal-title":"FASEB J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1177\/2050640619846011","article-title":"Pancreas-specific plasma amylase for assessment and diagnosis of chronic pancreatitis: New insights on an old topic","volume":"7","author":"Olesen","year":"2019","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"878","DOI":"10.5009\/gnl17066","article-title":"Low Serum Pancreatic Amylase and Lipase Values Are Simple and Useful Predictors to Diagnose Chronic Pancreatitis","volume":"11","author":"Oh","year":"2017","journal-title":"Gut Liver"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.3748\/wjg.v22.i10.2960","article-title":"Pathophysiology of chronic pancreatitis induced by dibutyltin dichloride joint ethanol in mice","volume":"22","author":"Zhang","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6357","DOI":"10.1038\/s41598-022-09595-x","article-title":"Misfolding-induced chronic pancreatitis in CPA1 N256K mutant mice is unaffected by global deletion of Ddit3\/Chop","volume":"12","author":"Nemeth","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1159\/000485906","article-title":"Hydrogen Treatment Protects Mice Against Chronic Pancreatitis by Restoring Regulatory T Cells Loss","volume":"44","author":"Chen","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5033","DOI":"10.1038\/s41467-018-07347-y","article-title":"A preclinical model of chronic pancreatitis driven by trypsinogen autoactivation","volume":"9","author":"Geisz","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.ccell.2016.02.005","article-title":"KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis","volume":"29","author":"Wei","year":"2016","journal-title":"Cancer Cell."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1159\/000488426","article-title":"Kruppel-Like Factor 4 Inhibits Pancreatic Cancer Epithelial-to-Mesenchymal Transition and Metastasis by Down-Regulating Caveolin-1 Expression","volume":"46","author":"Zhu","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.3892\/ijo.2017.4099","article-title":"Novel crosstalk between KLF4 and ZEB1 regulates gemcitabine resistance in pancreatic ductal adenocarcinoma","volume":"51","author":"Wang","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1158\/1078-0432.CCR-16-1064","article-title":"The Novel KLF4\/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer","volume":"23","author":"Guo","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.7150\/jca.38616","article-title":"Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer","volume":"11","author":"Jin","year":"2020","journal-title":"J. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1172\/JCI119714","article-title":"Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha. Role in regulating cell death and pancreatitis","volume":"100","author":"Gukovskaya","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1093\/emboj\/16.10.2621","article-title":"Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas","volume":"16","author":"Bottinger","year":"1997","journal-title":"EMBO J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1177\/145749690509400203","article-title":"Inflammatory response on the pancreatic acinar cell injury","volume":"94","author":"Bhatia","year":"2005","journal-title":"Scand. J. Surg."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1136\/gut.2006.105833","article-title":"Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations","volume":"56","author":"Wildi","year":"2007","journal-title":"Gut"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1053\/j.gastro.2018.02.030","article-title":"Neuronal Transforming Growth Factor beta Signaling via SMAD3 Contributes to Pain in Animal Models of Chronic Pancreatitis","volume":"154","author":"Liu","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1158\/0008-5472.CAN-15-1293","article-title":"TGFbeta Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis","volume":"76","author":"Principe","year":"2016","journal-title":"Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"30904","DOI":"10.1038\/srep30904","article-title":"TGF-beta1 promotes acinar to ductal metaplasia of human pancreatic acinar cells","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_80","first-page":"2751","article-title":"TGFbeta and the extracellular matrix in pancreatitis","volume":"46","author":"Menke","year":"1999","journal-title":"Hepatogastroenterology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1038\/onc.2015.263","article-title":"KLF5 promotes breast cancer proliferation, migration and invasion in part by upregulating the transcription of TNFAIP2","volume":"35","author":"Jia","year":"2016","journal-title":"Oncogene"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"15683","DOI":"10.1038\/s41598-017-15979-1","article-title":"KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression","volume":"7","author":"Ma","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e028999","DOI":"10.1136\/bmjopen-2019-028999","article-title":"Characterisation of the fibroinflammatory process involved in progression from acute to chronic pancreatitis: Study protocol for a multicentre, prospective cohort study","volume":"9","author":"Novovic","year":"2019","journal-title":"BMJ Open"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0140-6736(20)31318-0","article-title":"Chronic pancreatitis","volume":"396","author":"Beyer","year":"2020","journal-title":"Lancet"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.4049\/jimmunol.172.3.1872","article-title":"The C10\/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling","volume":"172","author":"Ma","year":"2004","journal-title":"J. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.ajpath.2013.05.020","article-title":"Differences in the degree of cerulein-induced chronic pancreatitis in C57BL\/6 mouse substrains lead to new insights in identification of potential risk factors in the development of chronic pancreatitis","volume":"183","author":"Ulmasov","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13287-016-0388-y","article-title":"Chemotaxis-driven disease-site targeting of therapeutic adult stem cells in dystrophic epidermolysis bullosa","volume":"7","author":"Alexeev","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.4049\/jimmunol.1302383","article-title":"Iddm30 controls pancreatic expression of Ccl11 (Eotaxin) and the Th1\/Th2 balance within the insulitic lesions","volume":"192","author":"Chao","year":"2014","journal-title":"J. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"G211","DOI":"10.1152\/ajpgi.00210.2017","article-title":"Role of eosinophils in the initiation and progression of pancreatitis pathogenesis","volume":"314","author":"Manohar","year":"2018","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1084\/jem.20142162","article-title":"TLR9 ligation in pancreatic stellate cells promotes tumorigenesis","volume":"212","author":"Zambirinis","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Zhang, L., Wang, D., Li, Y., Liu, Y., Xie, X., Wu, Y., Zhou, Y., Ren, J., Zhang, J., and Zhu, H. (2016). CCL21\/CCR7 Axis Contributed to CD133+ Pancreatic Cancer Stem-Like Cell Metastasis via EMT and Erk\/NF-kappaB Pathway. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158529"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1053\/j.gastro.2020.04.037","article-title":"CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated with Pain in Patients","volume":"159","author":"Hirth","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"4040","DOI":"10.1038\/s41598-019-40481-1","article-title":"Adult human pancreatic acinar cells dedifferentiate into an embryonic progenitor-like state in 3D suspension culture","volume":"9","author":"Baldan","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1136\/gut.2007.135665","article-title":"Adiponectin plays a protective role in caerulein-induced acute pancreatitis in mice fed a high-fat diet","volume":"57","author":"Araki","year":"2008","journal-title":"Gut"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.cca.2007.01.026","article-title":"Adiponectin as an anti-inflammatory factor","volume":"380","author":"Ouchi","year":"2007","journal-title":"Clin. Chim. Acta"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1097\/00041433-200312000-00003","article-title":"Obesity, adiponectin and vascular inflammatory disease","volume":"14","author":"Ouchi","year":"2003","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1016\/j.cmet.2022.09.024","article-title":"The gut peptide Reg3g links the small intestine microbiome to the regulation of energy balance, glucose levels, and gut function","volume":"34","author":"Shin","year":"2022","journal-title":"Cell. Metab."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3656","DOI":"10.1007\/s10620-015-3787-5","article-title":"Reg3g Promotes Pancreatic Carcinogenesis in a Murine Model of Chronic Pancreatitis","volume":"60","author":"Yin","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3078","DOI":"10.1111\/bph.15803","article-title":"Regenerating islet-derived protein 3 gamma (Reg3g) ameliorates tacrolimus-induced pancreatic beta-cell dysfunction in mice by restoring mitochondrial function","volume":"179","author":"Li","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/21623945.2019.1701394","article-title":"Unspecific DNA recombination in AdipoqCre-ER(T2) mediated knockout approaches in transgenic mice is sex-, age- and genotype-dependent","volume":"9","author":"Lindhorst","year":"2020","journal-title":"Adipocyte"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1002\/2211-5463.12714","article-title":"Tamoxifen affects chronic pancreatitis-related fibrogenesis in an experimental mouse model: An effect beyond Cre recombination","volume":"9","author":"Li","year":"2019","journal-title":"FEBS Open Bio"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1007\/s00204-018-2254-4","article-title":"Confounding influence of tamoxifen in mouse models of Cre recombinase-induced gene activity or modulation","volume":"92","author":"Hammad","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s12079-017-0390-x","article-title":"Tamoxifen for induction of Cre-recombination may confound fibrosis studies in female mice","volume":"11","author":"Falke","year":"2017","journal-title":"J. Cell Commun. Signal."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Reinert, R.B., Kantz, J., Misfeldt, A.A., Poffenberger, G., Gannon, M., Brissova, M., and Powers, A.C. (2012). Tamoxifen-Induced Cre-loxP Recombination Is Prolonged in Pancreatic Islets of Adult Mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033529"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/22\/5427\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:23:22Z","timestamp":1760131402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/22\/5427"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,15]]},"references-count":104,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["cancers15225427"],"URL":"https:\/\/doi.org\/10.3390\/cancers15225427","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,15]]}}}