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Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2/ITGB7/FAK axis

Abstract

Evidence suggests that tripartite motif-containing 2 (TRIM2) is associated with carcinogenic effects in several malignancies. However, the expression patterns and roles of TRIM2 in pancreatic cancer are rarely studied. Our study demonstrated that TRIM2 was expressed in a high percentage of pancreatic tumors. High TRIM2 expression was negatively correlated with the outcome of pancreatic cancer. TRIM2 silencing significantly inhibited the proliferation, migration, invasion, and in vivo tumorigenicity of pancreatic cancer cells. Regarding the mechanism involved, TRIM2 activated ROS-related E2-related factor 2 (NRF2)/antioxidant response element (ARE) signaling and the integrin/focal adhesion kinase (FAK) pathway. Treatment of pancreatic cancer cells with the antioxidant N-acetyl-L-cysteine decreased ROS activity and expression level of NRF2 and ITGB7. Increased translocation of NRF2 protein into nucleus further rescued the inhibited ITGB7 transcription. Moreover, NRF2 bound to the potential ARE on the promoter region and enhanced the transcriptional activity of ITGB7, indicating the bridging effect of NRF2 between the two signaling pathways. In summary, our study provides evidence that upregulated TRIM2 in pancreatic cancer predicts short survival for pancreatic cancer patients. TRIM2 accelerates pancreatic cancer progression via the ROS-related NRF2/ITGB7/FAK axis.

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Fig. 1: TRIM2 expression is correlated with a poor prognosis of PDAC.
Fig. 2: TRIM2 is required for cell proliferation and metastasis in PDAC.
Fig. 3: TRIM2 influences redox balance in pancreatic cancer cells.
Fig. 4: TRIM2 regulates NRF2/ARE activation in PDAC.
Fig. 5: Silencing TRIM2 suppresses integrin/FAK signaling.
Fig. 6: ITGB7 transcription is regulated in an ROS-related NRF2-dependent manner.
Fig. 7: Increased TRIM2 in pancreatic cancer cells promoted cell progression by ROS-related NRF2/ITGB7/FAK axis.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    PubMed  Google Scholar 

  2. Midha S, Chawla S, Garg PK. Modifiable and non-modifiable risk factors for pancreatic cancer: a review. Cancer Lett. 2016;381:269–77.

    CAS  PubMed  Google Scholar 

  3. Moore A, Donahue T. Pancreatic cancer. Jama 2019;322:1426.

    PubMed  PubMed Central  Google Scholar 

  4. Hatakeyama S. TRIM proteins and cancer. Nat Rev Cancer 2011;11:792–804.

    CAS  PubMed  Google Scholar 

  5. Watanabe M, Hatakeyama S. TRIM proteins and diseases. J Biochem. 2017;161:135–44.

    CAS  PubMed  Google Scholar 

  6. Masuda Y, Takahashi H, Sato S, Tomomori-Sato C, Saraf A, Washburn MP, et al. TRIM29 regulates the assembly of DNA repair proteins into damaged chromatin. Nat Commun. 2015;6:7299.

    CAS  PubMed  Google Scholar 

  7. Watanabe M, Tsukiyama T, Hatakeyama S. TRIM31 interacts with p52(Shc) and inhibits Src-induced anchorage-independent growth. Biochem Biophys Res Commun. 2009;388:422–7.

    CAS  PubMed  Google Scholar 

  8. Sato T, Okumura F, Ariga T, Hatakeyama S. TRIM6 interacts with Myc and maintains the pluripotency of mouse embryonic stem cells. J Cell Sci. 2012;125:1544–55.

    CAS  PubMed  Google Scholar 

  9. Yin H, Zhu Q, Liu M, Tu G, Li Q, Yuan J, et al. GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis. Int J Oncol. 2017;51:1191–8.

    CAS  PubMed  Google Scholar 

  10. Cao H, Fang Y, Liang Q, Wang J, Luo B, Zeng G, et al. TRIM2 is a novel promoter of human colorectal cancer. Scand J Gastroenterol. 2019;54:210–8.

    CAS  PubMed  Google Scholar 

  11. Qin Y, Ye J, Zhao F, Hu S, Wang S. TRIM2 regulates the development and metastasis of tumorous cells of osteosarcoma. Int J Oncol. 2018;53:1643–56.

    CAS  PubMed  Google Scholar 

  12. Ji S, Qin Y, Liang C, Huang R, Shi S, Liu J, et al. FBW7 (F-box and WD Repeat Domain-Containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) axis in pancreatic cancer. Clin Cancer Res. 2016;22:3950–60.

    CAS  PubMed  Google Scholar 

  13. Ji S, Qin Y, Shi S, Liu X, Hu H, Zhou H, et al. ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer. Cell Res. 2015;25:561–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hu Q, Qin Y, Zhang B, Liang C, Ji S, Shi S, et al. FBW7 increases the chemosensitivity of pancreatic cancer cells to gemcitabine through upregulation of ENT1. Oncol Rep. 2017;38:2069–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Qin Y, Hu Q, Xu J, Ji S, Dai W, Liu W, et al. PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis. Cell Commun Signal 2019;17:30.

    PubMed  PubMed Central  Google Scholar 

  16. Wang L, Heidt DG, Lee CJ, Yang H, Logsdon CD, Zhang L, et al. Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization. Cancer Cell 2009;15:207–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang L, Yang H, Palmbos PL, Ney G, Detzler TA, Coleman D, et al. ATDC/TRIM29 phosphorylation by ATM/MAPKAP kinase 2 mediates radioresistance in pancreatic cancer cells. Cancer Res. 2014;74:1778–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang L, Yang H, Zamperone A, Diolaiti D, Palmbos PL, Abel EV, et al. ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis. Genes Dev. 2019;33:641–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Martinez-Useros J, Li W, Cabeza-Morales M, Garcia-Foncillas J. Oxidative stress: a new target for pancreatic cancer prognosis and treatment. J Clin Med. 2017;6:29.

    PubMed Central  Google Scholar 

  20. Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer 2012;12:564–71.

    CAS  PubMed  Google Scholar 

  21. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 2011;16:123–40.

    CAS  PubMed  Google Scholar 

  22. Hayes AJ, Skouras C, Haugk B, Charnley RM. Keap1-Nrf2 signalling in pancreatic cancer. Int J Biochem Cell Biol. 2015;65:288–99.

    CAS  PubMed  Google Scholar 

  23. Chen X, Jiang Z, Zhou C, Chen K, Li X, Wang Z, et al. Activation of Nrf2 by sulforaphane inhibits high glucose-induced progression of pancreatic cancer via AMPK dependent signaling. Cell Physiol Biochem. 2018;50:1201–15.

    CAS  PubMed  Google Scholar 

  24. Chio IIC, Jafarnejad SM, Ponz-Sarvise M, Park Y, Rivera K, Palm W, et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic. Cancer Cell 2016;166:963–76.

    CAS  Google Scholar 

  25. Duong HQ, You KS, Oh S, Kwak SJ, Seong YS. Silencing of NRF2 reduces the expression of ALDH1A1 and ALDH3A1 and sensitizes to 5-FU in pancreatic cancer cells. Antioxidants (Basel). 2017;6:52.

    Google Scholar 

  26. Hamada S, Taguchi K, Masamune A, Yamamoto M, Shimosegawa T. Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis. Carcinogenesis 2017;38:661–70.

    CAS  PubMed  Google Scholar 

  27. Wakabayashi N, Shin S, Slocum SL, Agoston ES, Wakabayashi J, Kwak MK, et al. Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci Signal 2010;3:ra52.

    PubMed  PubMed Central  Google Scholar 

  28. Abukhdeir AM, Park BH. P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med. 2008;10:e19.

    PubMed  PubMed Central  Google Scholar 

  29. Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med. 2015;88:179–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hamidi H, Ivaska J. Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer 2018;18:533–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu Q, Qin Y, Xiang J, Liu W, Xu W, Sun Q, et al. dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer. Cell Prolif. 2018;51:e12456.

    PubMed  PubMed Central  Google Scholar 

  32. Theodore M, Kawai Y, Yang J, Kleshchenko Y, Reddy SP, Villalta F, et al. Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2. J Biol Chem. 2008;283:8984–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lin Z, Lin X, Zhu L, Huang J, Huang Y. TRIM2 directly deubiquitinates and stabilizes Snail1 protein, mediating proliferation and metastasis of lung adenocarcinoma. Cancer Cell Int. 2020;20:228.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Xiao W, Wang X, Wang T, Xing J. TRIM2 downregulation in clear cell renal cell carcinoma affects cell proliferation, migration, and invasion and predicts poor patients’ survival. Cancer Manag Res. 2018;10:5951–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Thompson S, Pearson AN, Ashley MD, Jessick V, Murphy BM, Gafken P, et al. Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection. J Biol Chem. 2011;286:19331–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Venuto S, Merla G. E3 ubiquitin ligase TRIM proteins, cell cycle and mitosis. Cells. 2019;8:510.

    PubMed Central  Google Scholar 

  37. Zoranovic T, Grmai L, Bach EA. Regulation of proliferation, cell competition, and cellular growth by the Drosophila JAK-STAT pathway. Jakstat 2013;2:e25408.

    PubMed  PubMed Central  Google Scholar 

  38. Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, et al. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia 2008;10:287–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Caratozzolo MF, Micale L, Turturo MG, Cornacchia S, Fusco C, Marzano F, et al. TRIM8 modulates p53 activity to dictate cell cycle arrest. Cell Cycle 2012;11:511–23.

    CAS  PubMed  Google Scholar 

  40. Qi ZX, Cai JJ, Chen LC, Yue Q, Gong Y, Yao Y, et al. TRIM28 as an independent prognostic marker plays critical roles in glioma progression. J Neurooncol. 2016;126:19–26.

    CAS  PubMed  Google Scholar 

  41. Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018;1865:721–33.

    CAS  PubMed  Google Scholar 

  42. Soini Y, Eskelinen M, Juvonen P, Karja V, Haapasaari KM, Saarela A, et al. Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma. Pathol Res Pract. 2014;210:35–39.

    CAS  PubMed  Google Scholar 

  43. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011;475:106–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Krajka-Kuzniak V, Paluszczak J, Baer-Dubowska W. The Nrf2-ARE signaling pathway: an update on its regulation and possible role in cancer prevention and treatment. Pharm Rep. 2017;69:393–402.

    CAS  Google Scholar 

  45. Logsdon CD, Simeone DM, Binkley C, Arumugam T, Greenson JK, Giordano TJ, et al. Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res. 2003;63:2649–57.

    CAS  PubMed  Google Scholar 

  46. Lister A, Nedjadi T, Kitteringham NR, Campbell F, Costello E, Lloyd B, et al. Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer 2011;10:37.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Reigan P, Colucci MA, Siegel D, Chilloux A, Moody CJ, Ross D. Development of indolequinone mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1): NQO1 inhibition and growth inhibitory activity in human pancreatic MIA PaCa-2 cancer cells. Biochemistry 2007;46:5941–50.

    CAS  PubMed  Google Scholar 

  48. Duong HQ, Yi YW, Kang HJ, Hong YB, Tang W, Wang A, et al. Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int J Oncol. 2014;44:959–69.

    CAS  PubMed  Google Scholar 

  49. Ough M, Lewis A, Bey EA, Gao J, Ritchie JM, Bornmann W, et al. Efficacy of beta-lapachone in pancreatic cancer treatment: exploiting the novel, therapeutic target NQO1. Cancer Biol Ther. 2005;4:95–102.

    CAS  PubMed  Google Scholar 

  50. Zhang W, Li H, Yang Y, Liao J, Yang GY. Knockdown or inhibition of aldo-keto reductase 1B10 inhibits pancreatic carcinoma growth via modulating Kras-E-cadherin pathway. Cancer Lett. 2014;355:273–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Arlt A, Sebens S, Krebs S, Geismann C, Grossmann M, Kruse ML, et al. Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 2013;32:4825–35.

    CAS  PubMed  Google Scholar 

  52. Wei L, Zhang JS, Ji SF, Xu H, Zhao ZH, Zhang L, et al. Knockdown of TRIM32 protects hippocampal neurons from oxygen-glucose deprivation-induced injury. Neurochem Res. 2019;44:2182–9.

    CAS  PubMed  Google Scholar 

  53. Tomar D, Prajapati P, Lavie J, Singh K, Lakshmi S, Bhatelia K, et al. TRIM4; a novel mitochondrial interacting RING E3 ligase, sensitizes the cells to hydrogen peroxide (H2O2) induced cell death. Free Radic Biol Med. 2015;89:1036–48.

    CAS  PubMed  Google Scholar 

  54. Ge W, Zhao K, Wang X, Li H, Yu M, He M, et al. iASPP is an antioxidative factor and drives cancer growth and drug resistance by competing with Nrf2 for Keap1 Binding. Cancer Cell 2017;32:561. e566

    CAS  PubMed  Google Scholar 

  55. Balastik M, Ferraguti F, Pires-da Silva A, Lee TH, Alvarez-Bolado G, Lu KP, et al. Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc Natl Acad Sci USA 2008;105:12016–21.

    CAS  PubMed  Google Scholar 

  56. Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21:363–83.

    CAS  PubMed  Google Scholar 

  57. Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, et al. KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell 2009;36:131–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Bui CB, Shin J. Persistent expression of Nqo1 by p62-mediated Nrf2 activation facilitates p53-dependent mitotic catastrophe. Biochem Biophys Res Commun. 2011;412:347–52.

    CAS  PubMed  Google Scholar 

  59. You A, Nam CW, Wakabayashi N, Yamamoto M, Kensler TW, Kwak MK. Transcription factor Nrf2 maintains the basal expression of Mdm2: an implication of the regulation of p53 signaling by Nrf2. Arch Biochem Biophys. 2011;507:356–64.

    CAS  PubMed  Google Scholar 

  60. Shibata T, Saito S, Kokubu A, Suzuki T, Yamamoto M, Hirohashi S. Global downstream pathway analysis reveals a dependence of oncogenic NF-E2-related factor 2 mutation on the mTOR growth signaling pathway. Cancer Res. 2010;70:9095–105.

    CAS  PubMed  Google Scholar 

  61. Niture SK, Jaiswal AK. Hsp90 interaction with INrf2(Keap1) mediates stress-induced Nrf2 activation. J Biol Chem. 2014;289:11568

    CAS  PubMed Central  Google Scholar 

  62. Kim H, Jung Y, Shin BS, Kim H, Song H, Bae SH, et al. Redox regulation of lipopolysaccharide-mediated sulfiredoxin induction, which depends on both AP-1 and Nrf2. J Biol Chem. 2010;285:34419–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Kuninty PR, Bansal R, De Geus SWL, Mardhian DF, Schnittert J, van Baarlen J, et al. ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer. Sci Adv. 2019;5:eaax2770.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Hedrick E, Lee SO, Safe S. The nuclear orphan receptor NR4A1 regulates beta1-integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists. Mol Carcinog. 2017;56:2066–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lu Y, Hu J, Sun W, Li S, Deng S, Li M. MiR-29c inhibits cell growth, invasion, and migration of pancreatic cancer by targeting ITGB1. Onco Targets Ther. 2016;9:99–109.

    CAS  PubMed  Google Scholar 

  66. Meng X, Liu P, Wu Y, Liu X, Huang Y, Yu B, et al. Integrin beta 4 (ITGB4) and its tyrosine-1510 phosphorylation promote pancreatic tumorigenesis and regulate the MEK1-ERK1/2 signaling pathway. Bosn J Basic Med Sci. 2020;20:106–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22:851–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kielosto M, Nummela P, Jarvinen K, Yin M, Holtta E. Identification of integrins alpha6 and beta7 as c-Jun- and transformation-relevant genes in highly invasive fibrosarcoma cells. Int J Cancer 2009;125:1065–73.

    CAS  PubMed  Google Scholar 

  69. Neri P, Ren L, Azab AK, Brentnall M, Gratton K, Klimowicz AC, et al. Integrin beta7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion. Blood 2011;117:6202–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Chai Z, Yang Y, Gu Z, Cai X, Ye W, Kong L, et al. Recombinant Viral Capsid Protein L2 (rVL2) of HPV 16 Suppresses Cell Proliferation and Glucose Metabolism via ITGB7/C/EBPbeta Signaling Pathway in Cervical Cancer Cell Lines. Onco Targets Ther. 2019;12:10415–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Farrow B, Rychahou P, O’Connor KL, Evers BM. Butyrate inhibits pancreatic cancer invasion. J Gastrointest Surg. 2003;7:864–70.

    PubMed  Google Scholar 

  72. Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B, Ohta M, et al. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-beta. Oncogene 2005;24:662–71.

    CAS  PubMed  Google Scholar 

  73. Chen X, Dong C, Law PT, Chan MT, Su Z, Wang S, et al. MicroRNA-145 targets TRIM2 and exerts tumor-suppressing functions in epithelial ovarian cancer. Gynecol Oncol. 2015;139:513–9.

    CAS  PubMed  Google Scholar 

  74. Schonrock N, Humphreys DT, Preiss T, Gotz J. Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-beta. J Mol Neurosci. 2012;46:324–35.

    CAS  PubMed  Google Scholar 

  75. Welcker M, Orian A, Jin J, Grim JE, Harper JW, Eisenman RN, et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA 2004;101:9085–90.

    CAS  PubMed  Google Scholar 

  76. Nateri AS, Riera-Sans L, Da Costa C, Behrens A. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science 2004;303:1374–8.

    CAS  PubMed  Google Scholar 

  77. Zhang Y, Xu J, Hua J, Liu J, Liang C, Meng Q, et al. A PD-L2-based immune marker signature helps to predict survival in resected pancreatic ductal adenocarcinoma. J Immunother Cancer 2019;7:233.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Meng Q, Shi S, Liang C, Liang D, Hua J, Zhang B, et al. Abrogation of glutathione peroxidase-1 drives EMT and chemoresistance in pancreatic cancer by activating ROS-mediated Akt/GSK3β/Snail signaling. Oncogene 2018;37:5843–57.

    CAS  PubMed  Google Scholar 

  79. Moffat J, Grueneberg DA, Yang X, Kim SY, Kloepfer AM, Hinkle G, et al. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 2006;124:1283–98.

    CAS  Google Scholar 

  80. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005;102:15545–50.

    CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (CN) (81871950 and 81972250); the China National Funds for Distinguished Young Scientists (CN) (81625016); the Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057).

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Conceptualization, XJY, QQS, XXW, SRJ and YQ; Methodology, QQS, GXF, XJY, ZY, ZZ and MQL; Statistical analysis, QQS, ZY, YQ and QFZ; Investigation, QQS, GXF, WYX, and WSL; Writing, QQS and YQ; Supervision, XJY, XWX and SRJ. All authors read and approved the final paper.

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Correspondence to Xiaowu Xu or Xianjun Yu.

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This study was approved by the Institutional Research Ethics Committee of Fudan University Shanghai Cancer Centre (ethical code: 050432-4-1212B) and written informed consent was obtained from all patients. All of the animal experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University (ethical code: 2019-JS-064).

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Sun, Q., Ye, Z., Qin, Y. et al. Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2/ITGB7/FAK axis. Oncogene 39, 6572–6588 (2020). https://doi.org/10.1038/s41388-020-01452-3

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