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An integrated epigenome and transcriptome analysis identifies PAX2 as a master regulator of drug resistance in high grade pancreatic ductal adenocarcinoma


Autoři: Imlimaong Aier aff001;  Rahul Semwal aff002;  Aiindrila Dhara aff003;  Nirmalya Sen aff003;  Pritish Kumar Varadwaj aff001
Působiště autorů: Department of Bioinformatics & Applied Sciences, Indian Institute of Information Technology—Allahabad, Uttar Pradesh, India aff001;  Department of Information Technology, Indian Institute of Information Technology—Allahabad, Uttar Pradesh, India aff002;  Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India aff003;  S.N.Bose Innovation Centre, University Of Kalyani, Nadia, West Bengal, India aff004
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0223554

Souhrn

Pancreatic ductal adenocarcinoma (PDAC) is notoriously difficult to treat due to its aggressive, ever resilient nature. A major drawback lies in its tumor grade; a phenomenon observed across various carcinomas, where highly differentiated and undifferentiated tumor grades, termed as low and high grade respectively, are found in the same tumor. One eminent problem due to such heterogeneity is drug resistance in PDAC. This has been implicated to ABC transporter family of proteins that are upregulated in PDAC patients. However, the regulation of these transporters with respect to tumor grade in PDAC is not well understood. To combat these issues, a study was designed to identify novel genes that might regulate drug resistance phenotype and be used as targets. By integrating epigenome with transcriptome data, several genes were identified based around high grade PDAC. Further analysis indicated oncogenic PAX2 transcription factor as a novel regulator of drug resistance in high grade PDAC cell lines. It was observed that silencing of PAX2 resulted in increased susceptibility of high grade PDAC cells to various chemotherapeutic drugs. Mechanistically, the study showed that PAX2 protein can bind and alter transcriptionally; expression of many ABC transporter genes in high grade PDAC cell lines. Overall, the study indicated that PAX2 significantly upregulated ABC family of genes resulting in drug resistance and poor survival in PDAC.

Klíčová slova:

Gene expression – Gene regulation – Genetic networks – Small interfering RNAs – Pancreatic cancer – Gene ontologies – Transcriptional control – Drug regulation


Zdroje

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians. 2016;66(1):7–30. doi: 10.3322/caac.21332 26742998.

2. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer research. 2014;74(11):2913–21. doi: 10.1158/0008-5472.CAN-14-0155 24840647.

3. Aier I, Semwal R, Sharma A, Varadwaj PK. A systematic assessment of statistics, risk factors, and underlying features involved in pancreatic cancer. Cancer epidemiology. 2019;58:104–10. doi: 10.1016/j.canep.2018.12.001 30537645.

4. Du Z, Qin R, Wei C, Wang M, Shi C, Tian R, et al. Pancreatic cancer cells resistant to chemoradiotherapy rich in "stem-cell-like" tumor cells. Digestive diseases and sciences. 2011;56(3):741–50. doi: 10.1007/s10620-010-1340-0 20683663.

5. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363(9414):1049–57. doi: 10.1016/S0140-6736(04)15841-8 15051286.

6. Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nature reviews Cancer. 2002;2(12):897–909. doi: 10.1038/nrc949 12459728.

7. Hidalgo M. Pancreatic cancer. The New England journal of medicine. 2010;362(17):1605–17. doi: 10.1056/NEJMra0901557 20427809.

8. Diaferia GR, Balestrieri C, Prosperini E, Nicoli P, Spaggiari P, Zerbi A, et al. Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer. The EMBO journal. 2016;35(6):595–617. doi: 10.15252/embj.201592404 26769127; PubMed Central PMCID: PMC4801945.

9. Kloppel G, Lingenthal G, von Bulow M, Kern HF. Histological and fine structural features of pancreatic ductal adenocarcinomas in relation to growth and prognosis: studies in xenografted tumours and clinico-histopathological correlation in a series of 75 cases. Histopathology. 1985;9(8):841–56. doi: 10.1111/j.1365-2559.1985.tb02870.x 2997015.

10. Karamitopoulou E. Role of epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma: is tumor budding the missing link? Frontiers in oncology. 2013;3:221. doi: 10.3389/fonc.2013.00221 24062980; PubMed Central PMCID: PMC3774985.

11. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer research. 2009;69(14):5820–8. doi: 10.1158/0008-5472.CAN-08-2819 19584296; PubMed Central PMCID: PMC4378690.

12. Konig J, Hartel M, Nies AT, Martignoni ME, Guo J, Buchler MW, et al. Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. International journal of cancer. 2005;115(3):359–67. doi: 10.1002/ijc.20831 15688370.

13. Hagmann W, Jesnowski R, Lohr JM. Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells. Neoplasia. 2010;12(9):740–7. doi: 10.1593/neo.10576 20824050; PubMed Central PMCID: PMC2933694.

14. Nambaru PK, Hubner T, Kock K, Mews S, Grube M, Payen L, et al. Drug efflux transporter multidrug resistance-associated protein 5 affects sensitivity of pancreatic cancer cell lines to the nucleoside anticancer drug 5-fluorouracil. Drug metabolism and disposition: the biological fate of chemicals. 2011;39(1):132–9. doi: 10.1124/dmd.110.033613 20930123.

15. Pratt S, Shepard RL, Kandasamy RA, Johnston PA, Perry W, Dantzig AH 3rd. The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Molecular cancer therapeutics. 2005;4(5):855–63. doi: 10.1158/1535-7163.MCT-04-0291 15897250.

16. Oguri T, Achiwa H, Sato S, Bessho Y, Takano Y, Miyazaki M, et al. The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: a role of ABCC5 in gemcitabine sensitivity. Molecular cancer therapeutics. 2006;5(7):1800–6. doi: 10.1158/1535-7163.MCT-06-0025 16891466.

17. Zelcer N, Saeki T, Reid G, Beijnen JH, Borst P. Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). The Journal of biological chemistry. 2001;276(49):46400–7. doi: 10.1074/jbc.M107041200 11581266.

18. Hagmann W, Faissner R, Schnolzer M, Lohr M, Jesnowski R. Membrane drug transporters and chemoresistance in human pancreatic carcinoma. Cancers. 2010;3(1):106–25. doi: 10.3390/cancers3010106 24212609; PubMed Central PMCID: PMC3756352.

19. Lee SH, Kim H, Hwang JH, Lee HS, Cho JY, Yoon YS, et al. Breast cancer resistance protein expression is associated with early recurrence and decreased survival in resectable pancreatic cancer patients. Pathology international. 2012;62(3):167–75. doi: 10.1111/j.1440-1827.2011.02772.x 22360504.

20. Le Large TYS, El Hassouni B, Kazemier G, Piersma SR, van Laarhoven HWM, Bijlsma MF, et al. Multidrug-resistant transporter expression does not always result in drug resistance. Cancer science. 2018;109(10):3360–2. doi: 10.1111/cas.13756 30195264; PubMed Central PMCID: PMC6172061.

21. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nature methods. 2015;12(4):357–60. doi: 10.1038/nmeth.3317 25751142; PubMed Central PMCID: PMC4655817.

22. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30(7):923–30. doi: 10.1093/bioinformatics/btt656 24227677.

23. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8 25516281; PubMed Central PMCID: PMC4302049.

24. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nature methods. 2012;9(4):357–9. doi: 10.1038/nmeth.1923 22388286; PubMed Central PMCID: PMC3322381.

25. Feng J, Liu T, Qin B, Zhang Y, Liu XS. Identifying ChIP-seq enrichment using MACS. Nature protocols. 2012;7(9):1728–40. doi: 10.1038/nprot.2012.101 22936215; PubMed Central PMCID: PMC3868217.

26. Ramirez F, Dundar F, Diehl S, Gruning BA, Manke T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic acids research. 2014;42(Web Server issue):W187–91. doi: 10.1093/nar/gku365 24799436; PubMed Central PMCID: PMC4086134.

27. Goecks J, Nekrutenko A, Taylor J, Galaxy T. Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences. Genome biology. 2010;11(8):R86. doi: 10.1186/gb-2010-11-8-r86 20738864; PubMed Central PMCID: PMC2945788.

28. Lerdrup M, Johansen JV, Agrawal-Singh S, Hansen K. An interactive environment for agile analysis and visualization of ChIP-sequencing data. Nature structural & molecular biology. 2016;23(4):349–57. doi: 10.1038/nsmb.3180 26926434.

29. Haeussler M, Zweig AS, Tyner C, Speir ML, Rosenbloom KR, Raney BJ, et al. The UCSC Genome Browser database: 2019 update. Nucleic acids research. 2019;47(D1):D853–D8. doi: 10.1093/nar/gky1095 30407534; PubMed Central PMCID: PMC6323953.

30. Wang S, Sun H, Ma J, Zang C, Wang C, Wang J, et al. Target analysis by integration of transcriptome and ChIP-seq data with BETA. Nature protocols. 2013;8(12):2502–15. doi: 10.1038/nprot.2013.150 24263090; PubMed Central PMCID: PMC4135175.

31. Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic acids research. 2009;37(1):1–13. doi: 10.1093/nar/gkn923 19033363; PubMed Central PMCID: PMC2615629.

32. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature genetics. 2000;25(1):25–9. doi: 10.1038/75556 10802651; PubMed Central PMCID: PMC3037419.

33. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome research. 2003;13(11):2498–504. doi: 10.1101/gr.1239303 14597658; PubMed Central PMCID: PMC403769.

34. Maere S, Heymans K, Kuiper M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 2005;21(16):3448–9. doi: 10.1093/bioinformatics/bti551 15972284.

35. Montojo J, Zuberi K, Rodriguez H, Kazi F, Wright G, Donaldson SL, et al. GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop. Bioinformatics. 2010;26(22):2927–8. doi: 10.1093/bioinformatics/btq562 20926419; PubMed Central PMCID: PMC2971582.

36. Pathan M, Keerthikumar S, Ang CS, Gangoda L, Quek CY, Williamson NA, et al. FunRich: An open access standalone functional enrichment and interaction network analysis tool. Proteomics. 2015;15(15):2597–601. doi: 10.1002/pmic.201400515 25921073.

37. Apweiler R, Bairoch A, Wu CH, Barker WC, Boeckmann B, Ferro S, et al. UniProt: the Universal Protein knowledgebase. Nucleic acids research. 2004;32(Database issue):D115–9. doi: 10.1093/nar/gkh131 14681372; PubMed Central PMCID: PMC308865.

38. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25(8):1091–3. doi: 10.1093/bioinformatics/btp101 19237447; PubMed Central PMCID: PMC2666812.

39. Luo W, Pant G, Bhavnasi YK, Blanchard SG Jr., Brouwer C. Pathview Web: user friendly pathway visualization and data integration. Nucleic acids research. 2017;45(W1):W501–W8. doi: 10.1093/nar/gkx372 28482075; PubMed Central PMCID: PMC5570256.

40. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40. doi: 10.1093/bioinformatics/btp616 19910308; PubMed Central PMCID: PMC2796818.

41. Le DH, Pham VH. HGPEC: a Cytoscape app for prediction of novel disease-gene and disease-disease associations and evidence collection based on a random walk on heterogeneous network. BMC systems biology. 2017;11(1):61. doi: 10.1186/s12918-017-0437-x 28619054; PubMed Central PMCID: PMC5472867.

42. Jia N, Wang J, Li Q, Tao X, Chang K, Hua K, et al. DNA methylation promotes paired box 2 expression via myeloid zinc finger 1 in endometrial cancer. Oncotarget. 2016;7(51):84785–97. doi: 10.18632/oncotarget.12626 27764784; PubMed Central PMCID: PMC5356698.

43. Kaku Y, Taguchi A, Tanigawa S, Haque F, Sakuma T, Yamamoto T, et al. PAX2 is dispensable for in vitro nephron formation from human induced pluripotent stem cells. Scientific reports. 2017;7(1):4554. doi: 10.1038/s41598-017-04813-3 28674456; PubMed Central PMCID: PMC5495778.

44. Larson Gedman A, Chen Q, Kugel Desmoulin S, Ge Y, LaFiura K, Haska CL, et al. The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia. 2009;23(8):1417–25. doi: 10.1038/leu.2009.64 19340001; PubMed Central PMCID: PMC2726275.

45. Huang YK, Fan XG, Qiu F. TM4SF1 Promotes Proliferation, Invasion, and Metastasis in Human Liver Cancer Cells. International journal of molecular sciences. 2016;17(5). doi: 10.3390/ijms17050661 27153056; PubMed Central PMCID: PMC4881487.

46. Kreft L, Soete A, Hulpiau P, Botzki A, Saeys Y, De Bleser P. ConTra v3: a tool to identify transcription factor binding sites across species, update 2017. Nucleic acids research. 2017;45(W1):W490–W4. doi: 10.1093/nar/gkx376 28472390; PubMed Central PMCID: PMC5570180.

47. Yevshin I, Sharipov R, Valeev T, Kel A, Kolpakov F. GTRD: a database of transcription factor binding sites identified by ChIP-seq experiments. Nucleic acids research. 2017;45(D1):D61–D7. doi: 10.1093/nar/gkw951 27924024; PubMed Central PMCID: PMC5210645.

48. Pinero J, Queralt-Rosinach N, Bravo A, Deu-Pons J, Bauer-Mehren A, Baron M, et al. DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes. Database: the journal of biological databases and curation. 2015;2015:bav028. doi: 10.1093/database/bav028 25877637; PubMed Central PMCID: PMC4397996.

49. Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, et al. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PloS one. 2012;7(10):e43192. doi: 10.1371/journal.pone.0043192 23071490; PubMed Central PMCID: PMC3468610.

50. Eccles MR, Wallis LJ, Fidler AE, Spurr NK, Goodfellow PJ, Reeve AE. Expression of the PAX2 gene in human fetal kidney and Wilms' tumor. Cell growth & differentiation: the molecular biology journal of the American Association for Cancer Research. 1992;3(5):279–89. 1378753.

51. Gokden N, Gokden M, Phan DC, McKenney JK. The utility of PAX-2 in distinguishing metastatic clear cell renal cell carcinoma from its morphologic mimics: an immunohistochemical study with comparison to renal cell carcinoma marker. The American journal of surgical pathology. 2008;32(10):1462–7. doi: 10.1097/PAS.0b013e318176dba7 18685487.

52. Doberstein K, Pfeilschifter J, Gutwein P. The transcription factor PAX2 regulates ADAM10 expression in renal cell carcinoma. Carcinogenesis. 2011;32(11):1713–23. doi: 10.1093/carcin/bgr195 21880579.

53. Wu H, Chen Y, Liang J, Shi B, Wu G, Zhang Y, et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature. 2005;438(7070):981–7. doi: 10.1038/nature04225 16355216.

54. Liu P, Gao Y, Huan J, Ge X, Tang Y, Shen W, et al. Upregulation of PAX2 promotes the metastasis of esophageal cancer through interleukin-5. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology. 2015;35(2):740–54. doi: 10.1159/000369734 25613757.

55. Buttiglieri S, Deregibus MC, Bravo S, Cassoni P, Chiarle R, Bussolati B, et al. Role of Pax2 in apoptosis resistance and proinvasive phenotype of Kaposi's sarcoma cells. The Journal of biological chemistry. 2004;279(6):4136–43. doi: 10.1074/jbc.M306824200 14627715.

56. Fonsato V, Buttiglieri S, Deregibus MC, Puntorieri V, Bussolati B, Camussi G. Expression of Pax2 in human renal tumor-derived endothelial cells sustains apoptosis resistance and angiogenesis. The American journal of pathology. 2006;168(2):706–13. doi: 10.2353/ajpath.2006.050776 16436683; PubMed Central PMCID: PMC1606486.

57. Cao J, Ma J, Sun L, Li J, Qin T, Zhou C, et al. Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/beta-catenin pathway in pancreatic cancer cells. Journal of cellular biochemistry. 2018;119(11):9498–512. doi: 10.1002/jcb.27266 30010221.

58. Wang W, Zhao L, Wei X, Wang L, Liu S, Yang Y, et al. MicroRNA-320a promotes 5-FU resistance in human pancreatic cancer cells. Scientific reports. 2016;6:27641. doi: 10.1038/srep27641 27279541; PubMed Central PMCID: PMC4899709.

59. Sun FX, Tohgo A, Bouvet M, Yagi S, Nassirpour R, Moossa AR, et al. Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model. Cancer research. 2003;63(1):80–5. 12517781.

60. Stathopoulos GP, Rigatos SK, Dimopoulos MA, Giannakakis T, Foutzilas G, Kouroussis C, et al. Treatment of pancreatic cancer with a combination of irinotecan (CPT-11) and gemcitabine: a multicenter phase II study by the Greek Cooperative Group for Pancreatic Cancer. Annals of oncology: official journal of the European Society for Medical Oncology. 2003;14(3):388–94. doi: 10.1093/annonc/mdg109 12598343.

61. Jeansonne DP, Koh GY, Zhang F, Kirk-Ballard H, Wolff L, Liu D, et al. Paclitaxel-induced apoptosis is blocked by camptothecin in human breast and pancreatic cancer cells. Oncology reports. 2011;25(5):1473–80. doi: 10.3892/or.2011.1187 21331447.

62. Fueger BJ, Hamilton G, Raderer M, Pangerl T, Traub T, Angelberger P, et al. Effects of chemotherapeutic agents on expression of somatostatin receptors in pancreatic tumor cells. Journal of nuclear medicine: official publication, Society of Nuclear Medicine. 2001;42(12):1856–62. 11752085.

63. Halloran CM, Ghaneh P, Shore S, Greenhalf W, Zumstein L, Wilson D, et al. 5-Fluorouracil or gemcitabine combined with adenoviral-mediated reintroduction of p16INK4A greatly enhanced cytotoxicity in Panc-1 pancreatic adenocarcinoma cells. The journal of gene medicine. 2004;6(5):514–25. doi: 10.1002/jgm.540 15133762.

64. Wang WB, Yang Y, Zhao YP, Zhang TP, Liao Q, Shu H. Recent studies of 5-fluorouracil resistance in pancreatic cancer. World journal of gastroenterology. 2014;20(42):15682–90. doi: 10.3748/wjg.v20.i42.15682 25400452; PubMed Central PMCID: PMC4229533.

65. Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. Jama. 2010;304(10):1073–81. doi: 10.1001/jama.2010.1275 20823433.

66. Damaraju VL, Damaraju S, Young JD, Baldwin SA, Mackey J, Sawyer MB, et al. Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy. Oncogene. 2003;22(47):7524–36. doi: 10.1038/sj.onc.1206952 14576856.

67. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. Inhibition of SRC tyrosine kinase impairs inherent and acquired gemcitabine resistance in human pancreatic adenocarcinoma cells. Clinical cancer research: an official journal of the American Association for Cancer Research. 2004;10(7):2307–18. 15073106.

68. Liau SS, Whang E. HMGA1 is a molecular determinant of chemoresistance to gemcitabine in pancreatic adenocarcinoma. Clinical cancer research: an official journal of the American Association for Cancer Research. 2008;14(5):1470–7. doi: 10.1158/1078-0432.CCR-07-1450 18316571; PubMed Central PMCID: PMC2652398.

69. Farrell JJ, Bae K, Wong J, Guha C, Dicker AP, Elsaleh H. Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704. The pharmacogenomics journal. 2012;12(5):395–403. doi: 10.1038/tpj.2011.22 21625252.

70. Nath S, Daneshvar K, Roy LD, Grover P, Kidiyoor A, Mosley L, et al. MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes. Oncogenesis. 2013;2:e51. doi: 10.1038/oncsis.2013.16 23774063; PubMed Central PMCID: PMC3740301.

71. Zhang W, Chen H, Liu DL, Li H, Luo J, Zhang JH, et al. Emodin sensitizes the gemcitabine-resistant cell line Bxpc-3/Gem to gemcitabine via downregulation of NF-kappaB and its regulated targets. International journal of oncology. 2013;42(4):1189–96. doi: 10.3892/ijo.2013.1839 23440366.

72. Aguirre-Gamboa R, Gomez-Rueda H, Martinez-Ledesma E, Martinez-Torteya A, Chacolla-Huaringa R, Rodriguez-Barrientos A, et al. SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis. PloS one. 2013;8(9):e74250. doi: 10.1371/journal.pone.0074250 24066126; PubMed Central PMCID: PMC3774754.

73. Stratford JK, Bentrem DJ, Anderson JM, Fan C, Volmar KA, Marron JS, et al. A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma. PLoS medicine. 2010;7(7):e1000307. doi: 10.1371/journal.pmed.1000307 20644708; PubMed Central PMCID: PMC2903589.

74. Zhang G, Schetter A, He P, Funamizu N, Gaedcke J, Ghadimi BM, et al. DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma. PloS one. 2012;7(2):e31507. doi: 10.1371/journal.pone.0031507 22363658; PubMed Central PMCID: PMC3282755.

75. Zhang G, He P, Tan H, Budhu A, Gaedcke J, Ghadimi BM, et al. Integration of metabolomics and transcriptomics revealed a fatty acid network exerting growth inhibitory effects in human pancreatic cancer. Clinical cancer research: an official journal of the American Association for Cancer Research. 2013;19(18):4983–93. doi: 10.1158/1078-0432.CCR-13-0209 23918603; PubMed Central PMCID: PMC3778077.

76. Swayden M, Iovanna J, Soubeyran P. Pancreatic cancer chemo-resistance is driven by tumor phenotype rather than tumor genotype. Heliyon. 2018;4(12):e01055. doi: 10.1016/j.heliyon.2018.e01055 30582059; PubMed Central PMCID: PMC6299038.

77. Mezencev R, Matyunina LV, Wagner GT, McDonald JF. Acquired resistance of pancreatic cancer cells to cisplatin is multifactorial with cell context-dependent involvement of resistance genes. Cancer gene therapy. 2016;23(12):446–53. doi: 10.1038/cgt.2016.71 27910856; PubMed Central PMCID: PMC5159445.

78. Gnanamony M, Gondi CS. Chemoresistance in pancreatic cancer: Emerging concepts. Oncology letters. 2017;13(4):2507–13. doi: 10.3892/ol.2017.5777 28454427; PubMed Central PMCID: PMC5403303.

79. Grasso C, Jansen G, Giovannetti E. Drug resistance in pancreatic cancer: Impact of altered energy metabolism. Critical reviews in oncology/hematology. 2017;114:139–52. doi: 10.1016/j.critrevonc.2017.03.026 28477742.

80. Gaianigo N, Melisi D, Carbone C. EMT and Treatment Resistance in Pancreatic Cancer. Cancers. 2017;9(9). doi: 10.3390/cancers9090122 28895920; PubMed Central PMCID: PMC5615337.

81. Andor N, Graham TA, Jansen M, Xia LC, Aktipis CA, Petritsch C, et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nature medicine. 2016;22(1):105–13. doi: 10.1038/nm.3984 26618723; PubMed Central PMCID: PMC4830693.

82. Hagmann W, Jesnowski R, Faissner R, Guo C, Lohr JM. ATP-binding cassette C transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Pancreatology: official journal of the International Association of Pancreatology. 2009;9(1–2):136–44. doi: 10.1159/000178884 19077464.

83. Cao J, Yang J, Ramachandran V, Arumugam T, Deng D, Li Z, et al. TM4SF1 Promotes Gemcitabine Resistance of Pancreatic Cancer In Vitro and In Vivo. PloS one. 2015;10(12):e0144969. doi: 10.1371/journal.pone.0144969 26709920; PubMed Central PMCID: PMC4692438.

84. Ireland L, Santos A, Ahmed MS, Rainer C, Nielsen SR, Quaranta V, et al. Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors. Cancer research. 2016;76(23):6851–63. doi: 10.1158/0008-5472.CAN-16-1201 27742686; PubMed Central PMCID: PMC5321488.

85. Ueda T, Ito S, Shiraishi T, Taniguchi H, Kayukawa N, Nakanishi H, et al. PAX2 promoted prostate cancer cell invasion through transcriptional regulation of HGF in an in vitro model. Biochimica et biophysica acta. 2015;1852(11):2467–73. doi: 10.1016/j.bbadis.2015.08.008 26296757.

86. Song H, Kwan SY, Izaguirre DI, Zu Z, Tsang YT, Tung CS, et al. PAX2 Expression in Ovarian Cancer. International journal of molecular sciences. 2013;14(3):6090–105. doi: 10.3390/ijms14036090 23502471; PubMed Central PMCID: PMC3634442.

87. Silberstein GB, Dressler GR, Van Horn K. Expression of the PAX2 oncogene in human breast cancer and its role in progesterone-dependent mammary growth. Oncogene. 2002;21(7):1009–16. doi: 10.1038/sj.onc.1205172 11850818.

88. Aslan M, Shahbazi R, Ulubayram K, Ozpolat B. Targeted Therapies for Pancreatic Cancer and Hurdles Ahead. Anticancer research. 2018;38(12):6591–606. doi: 10.21873/anticanres.13026 30504367.

89. Chand S, O'Hayer K, Blanco FF, Winter JM, Brody JR. The Landscape of Pancreatic Cancer Therapeutic Resistance Mechanisms. International journal of biological sciences. 2016;12(3):273–82. doi: 10.7150/ijbs.14951 26929734; PubMed Central PMCID: PMC4753156.

90. Bhagwandin VJ, Bishop JM, Wright WE, Shay JW. The Metastatic Potential and Chemoresistance of Human Pancreatic Cancer Stem Cells. PloS one. 2016;11(2):e0148807. doi: 10.1371/journal.pone.0148807 26859746; PubMed Central PMCID: PMC4747523.


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