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Identification of the Genetic Association Between Type-2-Diabetes and Pancreatic Cancer

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Abstract

Type-2-diabetes (T2D) and pancreatic cancer (PC) are both common diseases globally. Although T2D is reported as the adverse factor for predicting PC prognosis, its pathophysiology and relation with PC remain unknown. This study focused on exploring differentially expressed genes (DEGs) as well as their functional roles in T2D and PC, aiming to reveal the underlying association between the T2D and PC. To identify DEGs in T2D and PC, this study analyzed four microarray datasets obtained from Gene Expression Omnibus (GEO) database. Then, this work carried out enrichment as well as protein–protein interaction (PPI) network analysis for exploring DEGs-enriched functions and pathway. Besides, expression of hub genes was explored. TISIDB database was adopted to analyze the correlations among key gene and immune characteristics. Finally, the key gene expression was confirmed in vitro. DEGs were first screened from gene expression profiles of T2D and PC datasets, respectively. Then 135 common genes were identified in these four datasets. Based on functional analysis, common DEGs were mostly related to hormone secretion and metabolism pathways. Four hub genes were up-regulated, among which, MAFB was the most significant potential biomarker for PC. MAFB expression was strongly correlated with chemokines, chemokine receptors and immunomodulators. Finally, RT-qPCR was conducted to demonstrate the MAFB expression in T2D and PC. This study identified 15 hub genes with significant effects on the association of T2D with PC, and MAFB gene might be a biomarker for PC and had potential treatment value for PC.

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Data Availability

The data utilized in the present work can be obtained from corresponding author upon request.

References

  • Amin S, Mhango G, Lin J, Aronson A, Wisnivesky J, Boffetta P, Lucas AL (2016) metformin improves survival in patients with pancreatic ductal adenocarcinoma and pre-existing diabetes: a propensity score analysis. Am J Gastroenterol 111:1350–1357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andersen DK, Korc M, Petersen GM, Eibl G, Li D, Rickels MR, Chari ST, Abbruzzese JL (2017) Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66:1103–1110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bagchi S, Yuan R, Engleman EG (2021) Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol 16:223–249

    Article  CAS  PubMed  Google Scholar 

  • Bearrows SC, Bauchle CJ, Becker M, Haldeman JM, Swaminathan S, Stephens SB (2019) Chromogranin B regulates early-stage insulin granule trafficking from the Golgi in pancreatic islet β-cells. J Cell Sci. https://doi.org/10.1242/jcs.231373

    Article  PubMed  PubMed Central  Google Scholar 

  • Blandino-Rosano M, Barbaresso R, Jimenez-Palomares M, Bozadjieva N, Werneck-de-Castro JP, Hatanaka M, Mirmira RG, Sonenberg N, Liu M, Rüegg MA et al (2017) Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing. Nat Commun 8:16014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, Liu CG, Bhatt D, Taccioli C, Croce CM (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297:1901–1908

    Article  CAS  PubMed  Google Scholar 

  • Carreras-Torres R, Johansson M, Gaborieau V, Haycock PC, Wade KH, Relton CL, Martin RM, Davey Smith G, Brennan P (2017) The role of obesity, type 2 diabetes, and metabolic factors in pancreatic cancer: a mendelian randomization study. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djx012

    Article  PubMed  PubMed Central  Google Scholar 

  • Chatterjee S, Khunti K, Davies MJ (2017) Type 2 diabetes. Lancet 389:2239–2251

    Article  CAS  PubMed  Google Scholar 

  • Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY (2014) cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 8(Suppl 4):S11

    Article  PubMed  PubMed Central  Google Scholar 

  • Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4:P3

    Article  PubMed  Google Scholar 

  • Dominguez V, Raimondi C, Somanath S, Bugliani M, Loder MK, Edling CE, Divecha N, da Silva-Xavier G, Marselli L, Persaud SJ et al (2011) Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells. J Biol Chem 286:4216–4225

    Article  CAS  PubMed  Google Scholar 

  • Dooley J, Tian L, Schonefeldt S, Delghingaro-Augusto V, Garcia-Perez JE, Pasciuto E, Di Marino D, Carr EJ, Oskolkov N, Lyssenko V et al (2016) Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes. Nat Genet 48:519–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan L, Hu XQ, Feng DY, Lei SY, Hu GH (2013) GPC-1 may serve as a predictor of perineural invasion and a prognosticator of survival in pancreatic cancer. Asian J Surg 36:7–12

    Article  PubMed  Google Scholar 

  • Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13:759–771

    Article  CAS  PubMed  Google Scholar 

  • Ellsworth KA, Eckloff BW, Li L, Moon I, Fridley BL, Jenkins GD, Carlson E, Brisbin A, Abo R, Bamlet W et al (2013) Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic adenocarcinoma. PLoS ONE 8:e70216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Everhart J, Wright D (1995) Diabetes mellitus as a risk factor for pancreatic cancer. Meta-Anal Jama 273:1605–1609

    CAS  PubMed  Google Scholar 

  • Fuccio L, Hassan C, Laterza L, Correale L, Pagano N, Bocus P, Fabbri C, Maimone A, Cennamo V, Repici A et al (2013) The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. Gastrointest Endosc 78:596–608

    Article  PubMed  Google Scholar 

  • Grote VA, Becker S, Kaaks R (2010) Diabetes mellitus type 2—an independent risk factor for cancer? Exp Clin Endocrinol Diabetes 118:4–8

    Article  CAS  PubMed  Google Scholar 

  • Grote VA, Rohrmann S, Nieters A, Dossus L, Tjønneland A, Halkjær J, Overvad K, Fagherazzi G, Boutron-Ruault MC, Morois S et al (2011) Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: a study within the European prospective investigation into cancer and nutrition (EPIC) cohort. Diabetologia 54:3037–3046

    Article  CAS  PubMed  Google Scholar 

  • Gui JC, Yan WL, Liu XD (2014) CA19-9 and CA242 as tumor markers for the diagnosis of pancreatic cancer: a meta-analysis. Clin Exp Med 14:225–233

    Article  CAS  PubMed  Google Scholar 

  • Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, Robertson RP, Powers AC, Stein R (2013) Inactivation of specific β cell transcription factors in type 2 diabetes. J Clin Invest 123:3305–3316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotta K, Hosaka M, Tanabe A, Takeuchi T (2009) Secretogranin II binds to secretogranin III and forms secretory granules with orexin, neuropeptide Y, and POMC. J Endocrinol 202:111–121

    Article  CAS  PubMed  Google Scholar 

  • Howell K, Posluszny J, He LK, Szilagyi A, Halerz J, Gamelli RL, Shankar R, Muthu K (2012) High MafB expression following burn augments monocyte commitment and inhibits DC differentiation in hemopoietic progenitors. J Leukoc Biol 91:69–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang L, Jansen L, Balavarca Y, Molina-Montes E, Babaei M, van der Geest L, Lemmens V, Van Eycken L, De Schutter H, Johannesen TB et al (2019) Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. Gut 68:130–139

    Article  PubMed  Google Scholar 

  • Hughes CE, Nibbs RJB (2018) A guide to chemokines and their receptors. Febs j 285:2944–2971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Idichi T, Seki N, Kurahara H, Yonemori K, Osako Y, Arai T, Okato A, Kita Y, Arigami T, Mataki Y et al (2017) Regulation of actin-binding protein ANLN by antitumor miR-217 inhibits cancer cell aggressiveness in pancreatic ductal adenocarcinoma. Oncotarget 8:53180–53193

    Article  PubMed  PubMed Central  Google Scholar 

  • Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46:3–19

    Article  CAS  PubMed  Google Scholar 

  • Kang C, LeRoith D, Gallagher EJ (2018) Diabetes, obesity, and breast cancer. Endocrinology 159:3801–3812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karasinska JM, Topham JT, Kalloger SE, Jang GH, Denroche RE, Culibrk L, Williamson LM, Wong HL, Lee MKC, O’Kane GM et al (2020) Altered gene expression along the glycolysis-cholesterol synthesis axis is associated with outcome in pancreatic cancer. Clin Cancer Res 26:135–146

    Article  CAS  PubMed  Google Scholar 

  • Kawada T (2021) Diabetes mellitus and pancreatic cancer: a risk assessment. Clin Gastroenterol Hepatol 19:1304

    Article  PubMed  Google Scholar 

  • Khadka R, Tian W, Hao X, Koirala R (2018) Risk factor, early diagnosis and overall survival on outcome of association between pancreatic cancer and diabetes mellitus: changes and advances, a review. Int J Surg 52:342–346

    Article  PubMed  Google Scholar 

  • Kim NH, Chang Y, Lee SR, Ryu S, Kim HJ (2020) Glycemic status, insulin resistance, and risk of pancreatic cancer mortality in individuals with and without diabetes. Am J Gastroenterol 115:1840–1848

    Article  PubMed  Google Scholar 

  • Mandrekar JN (2010) Receiver operating characteristic curve in diagnostic test assessment. J Thorac Oncol 5:1315–1316

    Article  PubMed  Google Scholar 

  • Mehla K, Singh PK (2020) Metabolic subtyping for novel personalized therapies against pancreatic cancer. Clin Cancer Res 26:6–8

    Article  CAS  PubMed  Google Scholar 

  • Metzger P, Kirchleitner SV, Boehmer DFR, Hörth C, Eisele A, Ormanns S, Gunzer M, Lech M, Lauber K, Endres S et al (2020) Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model. Cancer Immunol Immunother 69:2101–2112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizrahi JD, Surana R, Valle JW, Shroff RT (2020) Pancreatic cancer. Lancet 395:2008–2020

    Article  CAS  PubMed  Google Scholar 

  • Moriguchi T, Hamada M, Morito N, Terunuma T, Hasegawa K, Zhang C, Yokomizo T, Esaki R, Kuroda E, Yoh K et al (2006) MafB is essential for renal development and F4/80 expression in macrophages. Mol Cell Biol 26:5715–5727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Neill RS, Stoita A (2021) Biomarkers in the diagnosis of pancreatic cancer: are we closer to finding the golden ticket? World J Gastroenterol 27:4045–4087

    Article  PubMed  PubMed Central  Google Scholar 

  • Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST (2008) Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 134:981–987

    Article  CAS  PubMed  Google Scholar 

  • Park JG, Tischfield MA, Nugent AA, Cheng L, Di Gioia SA, Chan WM, Maconachie G, Bosley TM, Summers CG, Hunter DG et al (2016) Loss of MAFB function in humans and mice causes Duane syndrome, aberrant extraocular muscle innervation, and inner-ear defects. Am J Hum Genet 98:1220–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park W, Chawla A, O’Reilly EM (2021) Pancreatic cancer: a review. JAMA 326:851–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS et al (2009) A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361:2019–2032

    Article  PubMed  Google Scholar 

  • Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928

    Article  CAS  PubMed  Google Scholar 

  • Poruk KE, Firpo MA, Scaife CL, Adler DG, Emerson LL, Boucher KM, Mulvihill SJ (2013) Serum osteopontin and tissue inhibitor of metalloproteinase 1 as diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. Pancreas 42:193–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin C, Yang G, Yang J, Ren B, Wang H, Chen G, Zhao F, You L, Wang W, Zhao Y (2020) Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Mol Cancer 19:50

    Article  PubMed  PubMed Central  Google Scholar 

  • Quoc Lam B, Shrivastava SK, Shrivastava A, Shankar S, Srivastava RK (2020) The Impact of obesity and diabetes mellitus on pancreatic cancer: molecular mechanisms and clinical perspectives. J Cell Mol Med 24:7706–7716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rawla P, Sunkara T, Gaduputi V (2019) Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol 10:10–27

    Article  PubMed  PubMed Central  Google Scholar 

  • Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47

    Article  PubMed  PubMed Central  Google Scholar 

  • Rozengurt E (2014) Mechanistic target of rapamycin (mTOR): a point of convergence in the action of insulin/IGF-1 and G protein-coupled receptor agonists in pancreatic cancer cells. Front Physiol 5:357

    Article  PubMed  PubMed Central  Google Scholar 

  • Ru B, Wong CN, Tong Y, Zhong JY, Zhong SSW, Wu WC, Chu KC, Wong CY, Lau CY, Chen I et al (2019) TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics 35:4200–4202

    Article  CAS  PubMed  Google Scholar 

  • Sato N, Fukushima N, Hruban RH, Goggins M (2008) CpG island methylation profile of pancreatic intraepithelial neoplasia. Mod Pathol 21:238–244

    Article  CAS  PubMed  Google Scholar 

  • Schreiber V, Mercier R, Jiménez S, Ye T, García-Sánchez E, Klein A, Meunier A, Ghimire S, Birck C, Jost B et al (2021) Extensive NEUROG3 occupancy in the human pancreatic endocrine gene regulatory network. Mol Metab 53:101313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shlomai G, Neel B, LeRoith D, Gallagher EJ (2016) Type 2 diabetes mellitus and cancer: the role of pharmacotherapy. J Clin Oncol 34:4261–4269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116:1793–1801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sing T, Sander O, Beerenwinkel N, Lengauer T (2005) ROCR: visualizing classifier performance in R. Bioinformatics 21:3940–3941

    Article  CAS  PubMed  Google Scholar 

  • Singh T, Colberg JK, Sarmiento L, Chaves P, Hansen L, Bsharat S, Cataldo LR, Dudenhöffer-Pfeifer M, Fex M, Bryder D et al (2019) Loss of MafA and MafB expression promotes islet inflammation. Sci Rep 9:9074

    Article  PubMed  PubMed Central  Google Scholar 

  • Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, Doncheva NT, Legeay M, Fang T, Bork P et al (2021) The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 49:D605-d612

    Article  CAS  PubMed  Google Scholar 

  • Takaori K, Bassi C, Biankin A, Brunner TB, Cataldo I, Campbell F, Cunningham D, Falconi M, Frampton AE, Furuse J et al (2016) International association of pancreatology (IAP)/European pancreatic club (EPC) consensus review of guidelines for the treatment of pancreatic cancer. Pancreatology 16:14–27

    Article  PubMed  Google Scholar 

  • Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45:W98-w102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang F, Gupta S, Holly EA (2006) Diabetes mellitus and pancreatic cancer in a population-based case-control study in the San Francisco Bay Area, California. Cancer Epidemiol Biomarkers Prev 15:1458–1463

    Article  PubMed  Google Scholar 

  • Wang X, Li Y, Tian H, Qi J, Li M, Fu C, Wu F, Wang Y, Cheng D, Zhao W et al (2014) Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma. BMC Cancer 14:578

    Article  PubMed  PubMed Central  Google Scholar 

  • Yadav MK, Inoue Y, Nakane-Otani A, Tsunakawa Y, Jeon H, Samir O, Teramoto A, Kulathunga K, Kusakabe M, Nakamura M et al (2020) Transcription factor MafB is a marker of tumor-associated macrophages in both mouse and humans. Biochem Biophys Res Commun 521:590–595

    Article  CAS  PubMed  Google Scholar 

  • Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, Wai-Sun Wong V, Yilmaz Y, George J, Fan J et al (2019) Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 69:2672–2682

    Article  PubMed  Google Scholar 

  • Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, Nwosu ZC, Halbrook CJ, Menjivar RE, Kemp SB, Sirihorachai VR et al (2020) Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov 10:422–439

    Article  PubMed  PubMed Central  Google Scholar 

  • Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14:88–98

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all the doctors in our department in the People’s Hospital of Leshan and this study was performed as a part of the employment.

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  1. Yaling Liang and Wei Chen have equally contributed to this work.

Authors and Affiliations

  1. Department of Geriatrics, The People’s Hospital of Leshan, 238 Baita Street, Leshan, 614000, People’s Republic of China

    Yaling Liang, Yun Tang & Meijuan Chen

  2. Emergency Department, The People’s Hospital of Leshan, Leshan, People’s Republic of China

    Wei Chen

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Contributions

Study concepts: YL. Study design: YL. Data analysis and preparation: YL, YT. Manuscript preparation: YT, WC, MC. Manuscript review: YL, YT, WC, MC. YL and WC share first authorship.

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Correspondence to Yaling Liang.

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10528_2022_10308_MOESM2_ESM.tiff

mRNA expression in PC patients (red; n= 179) and Normal control (black; n =171); (A) INS; (B) PCSK1; (C) GAD2; (D) GCG; (E) NEUROD1; (F) IAPP; (G) NKX2-2; (H) ABCC8; (I) SCG5; (J) SCG3; (K) INSM1.*Represents p value < 0.05. Supplementary file2 (TIFF 948 KB)

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Liang, Y., Chen, W., Tang, Y. et al. Identification of the Genetic Association Between Type-2-Diabetes and Pancreatic Cancer. Biochem Genet 61, 1143–1162 (2023). https://doi.org/10.1007/s10528-022-10308-2

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