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He Z, Khatib AM, Creemers JWM. The proprotein convertase furin in cancer: more than an oncogene. Oncogene. 2022;doi: 10.1038/s41388-021-02175-9.
He, Z., Khatib, A. M., & Creemers, J. W. M. (2022). The proprotein convertase furin in cancer: more than an oncogene. Oncogene, . https://doi.org/10.1038/s41388-021-02175-9
He, Zongsheng, et al. "The proprotein convertase furin in cancer: more than an oncogene." Oncogene vol. (2022). doi: https://doi.org/10.1038/s41388-021-02175-9
He Z, Khatib AM, Creemers JWM. The proprotein convertase furin in cancer: more than an oncogene. Oncogene. 2022 Jan 07; doi: 10.1038/s41388-021-02175-9. Epub 2022 Jan 07. PMID: 34997216.
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Oncogene. 2022 Jan 07; doi: 10.1038/s41388-021-02175-9. Epub 2022 Jan 07.

The proprotein convertase furin in cancer: more than an oncogene.

Oncogene

Zongsheng He, Abdel-Majid Khatib, John W M Creemers

Affiliations

  1. Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China.
  2. Laboratory of Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  3. INSERM, LAMC, UMR 1029, Allée Geoffroy St Hilaire, Pessac, France. [email protected].
  4. Institut Bergoinié, Bordeaux, France. [email protected].
  5. Laboratory of Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium. [email protected].

PMID: 34997216 DOI: 10.1038/s41388-021-02175-9

Abstract

Furin is the first discovered proprotein convertase member and is present in almost all mammalian cells. Therefore, by regulating the maturation of a wide range of proproteins, Furin expression and/or activity is involved in various physiological and pathophysiological processes ranging from embryonic development to carcinogenesis. Since many of these protein precursors are involved in initiating and maintaining the hallmarks of cancer, Furin has been proposed as a potential target for treating several human cancers. In contrast, other studies have revealed that some types of cancer do not benefit from Furin inhibition. Therefore, understanding the heterogeneous functions of Furin in cancer will provide important insights into the design of effective strategies targeting Furin in cancer treatment. Here, we present recent advances in understanding how Furin expression and activity are regulated in cancer cells and their influences on the activity of Furin substrates in carcinogenesis. Furthermore, we discuss how Furin represses tumorigenic properties of several cancer cells and why Furin inhibition leads to aggressive phenotypes in other tumors. Finally, we summarize the clinical applications of Furin inhibition in treating human cancers.

© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

References

  1. Puente XS, Sánchez LM, Overall CM, López-Otín C. Human and mouse proteases: a comparative genomic approach. Nat Rev Genet. 2003;4:544–58. - PubMed
  2. Shakya M, Lindberg I. Mouse models of human proprotein convertase insufficiency. Endocr Rev. 2021;42:259–94. - PubMed
  3. Roebroek AJM, Schalken JA, Bussemakers MJG, van Heerikhuizen H, Onnekink C, Debruyne FMJ, et al. Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene. Mol Biol Rep. 1986;11:117–25. - PubMed
  4. Roebroek AJ, Schalken JA, Leunissen JA, Onnekink C, Bloemers HP, Van, et al. Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein. EMBO J. 1986;5:2197–202. - PubMed
  5. Julius D, Brake A, Blair L, Kunisawa R, Thorner J. Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-alpha-factor. Cell. 1984;37:1075–89. - PubMed
  6. Van de Ven WJ, Creemers JW, Roebroek AJ. Furin: the prototype mammalian subtilisin-like proprotein-processing enzyme. Endoproteolytic cleavage at paired basic residues of proproteins of the eukaryotic secretory pathway. Enzyme. 1991;45:257–70. - PubMed
  7. Coppola I, Brouwers B, Meulemans S, Ramos-Molina B, Creemers JWM. Differential effects of furin deficiency on insulin receptor processing and glucose control in liver and pancreatic β cells of mice. Int J Mol Sci. 2021;22:6344. - PubMed
  8. Roebroek AJM, Taylor NA, Louagie E, Pauli I, Smeijers L, Snellinx A, et al. Limited redundancy of the proprotein convertase furin in mouse liver. J Biol Chem. 2004;279:53442–50. - PubMed
  9. Kara I, Poggi M, Bonardo B, Govers R, Landrier JF, Tian S, et al. The paired basic amino acid-cleaving enzyme 4 (PACE4) is involved in the maturation of insulin receptor isoform B: An opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2). J Biol Chem. 2015;290:2812–21. - PubMed
  10. He Z, Thorrez L, Siegfried G, Meulemans S, Evrard S, Tejpar S, et al. The proprotein convertase furin is a pro-oncogenic driver in KRAS and BRAF driven colorectal cancer. Oncogene. 2020;39:3571–87. - PubMed
  11. Tomé M, Pappalardo A, Soulet F, López JJ, Olaizola J, Leger Y, et al. Inactivation of proprotein convertases in T cells Inhibits PD-1 expression and creates a favorable immune microenvironment in colorectal cancer. Cancer Res. 2019;79:5008–21. - PubMed
  12. Khatib AM, Siegfried G, Prat A, Luis J, Chrétien M, Metrakos P, et al. Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells: Importance of insulin-like growth factor-1 (IGF-1) receptor processing in IGF-1-mediated functions. J Biol Chem. 2001;276:30686–93. - PubMed
  13. Scamuffa N, Siegfried G, Bontemps Y, Ma L, Basak A, Cherel G, et al. Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells. J Clin Invest. 2008;118:352–63. - PubMed
  14. Oh J, Barve M, Matthews CM, Koon EC, Heffernan TP, Fine B, et al. Phase II study of Vigil® DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer. Gynecol Oncol. 2016;143:504–10. - PubMed
  15. Rocconi RP, Stevens EE, Bottsford-Miller JN, Ghamande SA, Aaron P, Wallraven G, et al. A phase I combination study of vigil and atezolizumab in recurrent/refractory advanced-stage ovarian cancer: Efficacy assessment in BRCA1/2-wt patients. J Clin Oncol. 2020;38:3002. - PubMed
  16. Huang YH, Lin KH, Liao CH, Lai MW, Tseng YH, Yeh CT. Furin overexpression suppresses tumor growth and predicts a better postoperative disease-free survival in hepatocellular carcinoma. PLoS One. 2012;7:1–10. - PubMed
  17. Declercq J, Brouwers B, Pruniau VPEG, Stijnen P, Tuand K, Meulemans S, et al. Liver-specific inactivation of the proprotein convertase FURIN leads to increased hepatocellular carcinoma growth. Biomed Res Int. 2015;2015:148651. - PubMed
  18. Declercq J, Ramos-Molina B, Sannerud R, Brouwers B, Pruniau VPEG, Meulemans S. et al. Endosome to trans-Golgi network transport of proprotein convertase 7 is mediated by a cluster of basic amino acids and palmitoylated cysteines. Eur J Cell Biol. 2017;96:432–9. - PubMed
  19. Griffiths G, Simons K. The trans Golgi network: sorting at the exit site of the Golgi complex. Science. 1986;234:438–43. - PubMed
  20. Molloy SS, Anderson ED, Jean F, Thomas G. Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends Cell Biol. 1999;9:28–35. - PubMed
  21. Plaimauer B, Mohr G, Wernhart W, Himmelspach M, Dorner F, Schlokat U. ‘Shed’ furin: mapping of the cleavage determinants and identification of its C-terminus. Biochem J. 2001;354:689. - PubMed
  22. Mesnard D, Donnison M, Fuerer C, Pfeffer PL, Constam DB. The microenvironment patterns the pluripotent mouse epiblast through paracrine furin and Pace4 proteolytic activities. Genes Dev. 2011;25:1871–80. - PubMed
  23. Paleyanda RK, Drews R, Lee TK, Luboń H. Secretion of human furin into mouse milk. J Biol Chem. 1997;272:15270–4. - PubMed
  24. Ginefra P, Filippi BGH, Donovan P, Bessonnard S, Constam DB. Compartment-specific biosensors reveal a complementary subcellular distribution of bioactive Furin and PC7. Cell Rep. 2018;22:2176–89. - PubMed
  25. Susan-Resiga D, Essalmani R, Hamelin J, Asselin MC, Benjannet S, Chamberland A, et al. Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10. J Biol Chem. 2011;286:22785–94. - PubMed
  26. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419. - PubMed
  27. Uhlen M, Karlsson MJ, Zhong W, Tebani A, Pou C, Mikes J, et al. A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science. 2019;366:eaax9198. - PubMed
  28. Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, et al. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature. 2008;455:246–50. - PubMed
  29. van der Veeken J, Gonzalez AJ, Cho H, Arvey A, Hemmers S, Leslie CS, et al. Memory of inflammation in regulatory T cells. Cell. 2016;166:977–90. - PubMed
  30. Creemers JWM, Khatib A-M. Knock-out mouse models of proprotein convertases: unique functions or redundancy? Front Biosci. 2008;13:4960–71. - PubMed
  31. Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science. 2001;294:1945–8. - PubMed
  32. Cao J, Rehemtulla A, Pavlaki M, Kozarekar P, Chiarelli C. Furin directly cleaves proMMP-2 in the trans-golgi network resulting in a nonfunctioning proteinase. J Biol Chem. 2005;280:10974–80. - PubMed
  33. Soulet F, Bodineau C, Hooks KB, Descarpentrie J, Alves I, Dubreuil M, et al. ELA/APELA precursor cleaved by furin displays tumor suppressor function in renal cell carcinoma through mTORC1 activation. JCI Insight. 2020;5:e129070. - PubMed
  34. Tian S, Huang Q, Fang Y, Wu J. FurinDB: a database of 20-residue furin cleavage site motifs, substrates and their associated drugs. Int J Mol Sci. 2011;12:1060–5. - PubMed
  35. Shiryaev SA, Chernov AV, Golubkov VS, Thomsen ER, Chudin E, Chee MS, et al. High-resolution analysis and functional mapping of cleavage sites and substrate proteins of furin in the human proteome. PLoS One. 2013;8:1–12. - PubMed
  36. Siegfried G, Basak A, Prichett-Pejic W, Scamuffa N, Ma L, Benjannet S, et al. Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases. Oncogene. 2005;24:6925–35. - PubMed
  37. Scamuffa N, Sfaxi F, Ma J, Lalou C, Seidah N, Calvo F, et al. Prodomain of the proprotein convertase subtilisin/kexin Furin (ppFurin) protects from tumor progression and metastasis. Carcinogenesis. 2014;35:528–36. - PubMed
  38. He Z, Khatib A-M, Creemers JWM. Loss of proprotein convertase furin in mammary gland impairs proIGF1R and proIR processing and suppresses tumorigenesis in triple negative breast cancer. Cancers (Basel). 2020;12:2686. - PubMed
  39. He Z, Khatib A, Creemers JWM. Loss of the proprotein convertase Furin in T cells represses mammary tumorigenesis in oncogene-driven triple negative breast cancer. Cancer Lett. 2020;484:40–9. - PubMed
  40. Lapierre M, Siegfried G, Scamuffa N, Bontemps Y, Calvo F, Seidah NG, et al. Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells’ malignant phenotypes: Role of tissue inhibitors of metalloproteinase-1. Cancer Res. 2007;67:9030–4. - PubMed
  41. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. - PubMed
  42. Duguay SJ, Milewski WM, Young BD, Nakayama K, Steiner DF. Processing of wild-type and mutant proinsulin-like growth factor-IA by subtilisin-related proprotein convertases. J Biol Chem. 1997;272:6663–70. - PubMed
  43. Duguay SJ, Jin Y, Stein J, Duguay AN, Gardner P, Steiner DF. Post-translational processing of the insulin-like growth factor-2 precursor. Analysis of O-glycosylation and endoproteolysis. J Biol Chem. 1998;273:18443–51. - PubMed
  44. Liefers-Visser JAL, Meijering RAM, Reyners AKL, van der Zee AGJ, de Jong S. IGF system targeted therapy: Therapeutic opportunities for ovarian cancer. Cancer Treat Rev. 2017;60:90–9. - PubMed
  45. Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018;17:1–14. - PubMed
  46. Zhang Y, Zhou M, Wei H, Zhou H, He J, Lu Y, et al. Furin promotes epithelial-mesenchymal transition in pancreatic cancer cells via Hippo-YAP pathway. Int J Oncol. 2017;50:1352–62. - PubMed
  47. Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:0057–61. - PubMed
  48. Ramirez C, Hauser AD, Vucic EA, Bar-Sagi D. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis. Nature. 2019;576:477–81. - PubMed
  49. Louagie E, Taylor NA, Flamez D, Roebroek AJM, Bright NA, Meulemans S, et al. Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate. Proc Natl Acad Sci USA. 2008;105:12319–24. - PubMed
  50. Hasegawa-Minato J, Toyoshima M, Ishibashi M, Zhang X, Shigeta S, Grandori C, et al. Novel cooperative pathway of c-Myc and Furin, a pro-protein convertase, in cell proliferation as a therapeutic target in ovarian cancers. Oncotarget. 2018;9:3483–96. - PubMed
  51. De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17:457–74. - PubMed
  52. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 1997;16:3898–911. - PubMed
  53. McColl BK, Paavonen K, Karnezis T, Harris NC, Davydova N, Rothacker J, et al. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J. 2007;21:1088–98. - PubMed
  54. Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chrétien M, et al. The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest. 2003;111:1723–32. - PubMed
  55. Ma J, Evrard S, Badiola I, Siegfried G, Khatib A-M. Regulation of the proprotein convertases expression and activity during regenerative angiogenesis: Role of hypoxia-inducible factor (HIF). Eur J Cell Biol. 2017;96:457–68. - PubMed
  56. Khatib AM, Lahlil R, Hagedorn M, Delomenie C, Christophe O, Denis C, et al. Biological outcome and mapping of total factor cascades in response to HIF induction during regenerative angiogenesis. Oncotarget. 2016;7:12102–20. - PubMed
  57. Siegfried G, Khatib A-MM, Benjannet S, Chrétien M, Seidah NG. The proteolytic processing of pro-platelet-derived growth factor-a at RRKR86 by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity. Cancer Res. 2003;63:1458–63. - PubMed
  58. Jaaks P, D’Alessandro V, Grob N, Büel S, Hajdin K, Schäfer BW, et al. The proprotein convertase furin contributes to rhabdomyosarcoma malignancy by promoting vascularization, migration and invasion. PLoS One. 2016;11:e0161396. - PubMed
  59. Adams RH, Lohrum M, Klostermann A, Betz H, Püschel AW. The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. EMBO J. 1997;16:6077–86. - PubMed
  60. Mumblat Y, Kessler O, Ilan N, Neufeld G. Full-length semaphorin-3C is an inhibitor of tumor lymphangiogenesis and metastasis. Cancer Res. 2015;75:2177–86. - PubMed
  61. Doçi CL, Mikelis CM, Lionakis MS, Molinolo AA, Gutkind JS. Genetic identification of SEMA3F as an antilymphangiogenic metastasis suppressor gene in head and neck squamous carcinoma. Cancer Res. 2015;75:2937–48. - PubMed
  62. Parker MW, Hellman LM, Xu P, Fried MG, Vander Kooi CW. Furin processing of semaphorin 3F determines its anti-angiogenic activity by regulating direct binding and competition for neuropilin. Biochemistry. 2010;49:4068–75. - PubMed
  63. Varshavsky A, Kessler O, Abramovitch S, Kigel B, Zaffryar S, Akiri G, et al. Semaphorin-3B is an angiogenesis inhibitor that is inactivated by furin-like pro-protein convertases. Cancer Res. 2008;68:6922–31. - PubMed
  64. Christensen C, Ambartsumian N, Gilestro G, Thomsen B, Comoglio P, Tamagnone L, et al. Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 2005;65:6167–77. - PubMed
  65. Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E, et al. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med. 2012;4:234–50. - PubMed
  66. Sugano Y, Matsuzaki K, Tahashi Y, Furukawa F, Mori S, Yamagata H, et al. Distortion of autocrine transforming growth factor β signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells. Oncogene. 2003;22:2309–21. - PubMed
  67. McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM. Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem. 2006;281:24171–81. - PubMed
  68. Fu J, Zhang J, Gong Y, Testa CL, Klein-Szanto AJ. Regulation of HIF-1 alpha by the proprotein convertases furin and PC7 in human squamous carcinoma cells. Mol Carcinog. 2015;54:698–706. - PubMed
  69. Bommireddy R, Doetschman T. TGFβ1 and Treg cells: alliance for tolerance. Trends Mol Med. 2007;13:492–501. - PubMed
  70. Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2021;18:9–34. - PubMed
  71. Chen W, Ten Dijke P. Immunoregulation by members of the TGFβ superfamily. Nat Rev Immunol. 2016;16:723–40. - PubMed
  72. Ghisoli M, Barve M, Schneider R, Mennel R, Lenarsky C, Wallraven G, et al. Pilot trial of FANG immunotherapy in ewing’s sarcoma. Mol Ther. 2015;23:1103–9. - PubMed
  73. Nemunaitis J, Barve M, Orr D, Kuhn J, Magee M, Lamont J, et al. Summary of bi-shRNA furin /GM-CSF augmented autologous tumor cell immunotherapy (FANGTM) in advanced cancer of the liver. Oncol. 2014;87:21–9. - PubMed
  74. Blanchette F, Rudd P, Grondin F, Attisano L, Dubois CM. Involvement of Smads in TGFbeta1-induced furin (fur) transcription. J Cell Physiol. 2001;188:264–73. - PubMed
  75. Bilbao D, Luciani L, Johannesson B, Piszczek A, Rosenthal N. Insulin‐like growth factor‐1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol Med. 2014;6:1423–35. - PubMed
  76. Kusmartsev S, Gabrilovich DI. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother. 2006;55:237–45. - PubMed
  77. Cordova ZM, Grönholm A, Kytölä V, Taverniti V, Hämäläinen S, Aittomäki S, et al. Myeloid cell expressed proprotein convertase FURIN attenuates inflammation. Oncotarget. 2016;7:54392–404. - PubMed
  78. Rose M, Duhamel M, Rodet F, Salzet M. The role of proprotein convertases in the regulation of the function of immune cells in the oncoimmune response. Front Immunol. 2021;12:1–10. - PubMed
  79. DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019;19:369–82. - PubMed
  80. Vähätupa M, Aittomäki S, Martinez Cordova Z, May U, Prince S, Uusitalo-Järvinen H, et al. T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development. Oncoimmunology. 2016;5:1–11. - PubMed
  81. Lissitzky JC, Luis J, Munzer JS, Benjannet S, Parat F, Chrétien M, et al. Endoproteolytic processing of integrin pro-α subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7. Biochem J. 2000;346:133–8. - PubMed
  82. Bergeron E, Basak A, Decroly E, Seidah NG. Processing of α4 integrin by the proprotein convertases: Histidine at position P6 regulates cleavage. Biochem J. 2003;373:475–84. - PubMed
  83. Lehmann M, Rigot V, Seidah NG, Marvaldi J, Lissitzky JC. Lack of integrin α-chain endoproteolytic cleavage in furin-deficient human colon adenocarcinoma cells LoVo. Biochem J. 1996;317:803–9. - PubMed
  84. Felding-Habermann B, O’Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, et al. Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA. 2001;98:1853–8. - PubMed
  85. Sawada K, Mitra AK, Radjabi AR, Bhaskar V, Kistner EO, Tretiakova M, et al. Loss of E-cadherin promotes ovarian cancer metastasis via α5-integrin, which is a therapeutic target. Cancer Res. 2008;68:2329–39. - PubMed
  86. Posthaus H, Dubois CM, Laprise MH, Grondin F, Suter MM, Müller E. Proprotein cleavage of E-cadherin by furin in baculovirus over-expression system: Potential role of other convertases in mammalian cells. FEBS Lett. 1998;438:306–10. - PubMed
  87. Maret D, Gruzglin E, Sadr MS, Siu V, Shan W, Koch AW, et al. Surface expression of precursor N-cadherin promotes tumor cell invasion. Neoplasia. 2010;12:1066–80. - PubMed
  88. Yu W, Yang L, Li T, Zhang Y. Cadherin signaling in cancer: its functions and role as a therapeutic target. Front Oncol. 2019;9:989. - PubMed
  89. Duval S, Abu-Thuraia A, Elkholi IE, Chen R, Seebun D, Mayne J, et al. Shedding of cancer susceptibility candidate 4 by the convertases PC7/furin unravels a novel secretory protein implicated in cancer progression. Cell Death Dis. 2020;11:665. - PubMed
  90. Khatib AM, Kontogiannea M, Fallavollita L, Jamison B, Meterissian S, Brodt P. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res. 1999;59:1356–61. - PubMed
  91. Khatib AM, Auguste P, Fallavollita L, Wang N, Samani A, Kontogiannea M, et al. Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am J Pathol. 2005;167:749–59. - PubMed
  92. Takino T, Sato H, Shinagawa A, Seiki M. Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library: MT-MMPs form a unique membrane-type subclass in the MMP family. J Biol Chem. 1995;270:23013–20. - PubMed
  93. Pei D. Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP. J Biol Chem. 1999;274:8925–32. - PubMed
  94. Ueda J, Kajita M, Suenaga N, Fujii K, Seiki M. Sequence-specific silencing of MT1-MMP expression suppresses tumor cell migration and invasion: importance of MT1-MMP as a therapeutic target for invasive tumors. Oncogene. 2003;22:8716–22. - PubMed
  95. Khatib AM, Siegfried G, Chrétien M, Metrakos P, Seidah NG. Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. Am J Pathol. 2002;160:1921–35. - PubMed
  96. Bassi DE, Mahloogi H, Al-Saleem L, De Cicco RL, Ridge JA, Klein-Szanto AJP. Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. Mol Carcinog. 2001;31:224–32. - PubMed
  97. Bassi DE, De Cicco RL, Mahloogi H, Zucker S, Thomas G, Klein-Szanto AJP. Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells. Proc Natl Acad Sci USA. 2001;98:10326–31. - PubMed
  98. Loechel F, Gilpin BJ, Engvall E, Albrechtsen R, Wewer UM. Human ADAM 12 (Meltrin α) is an active metalloprotease. J Biol Chem. 1998;273:16993–7. - PubMed
  99. Schlöndorff J, Becherer JD, Blobel CP. Intracellular maturation and localization of the tumour necrosis factor α convertase (TACE). Biochem J. 2000;347:131–8. - PubMed
  100. Siegfried G, Descarpentrie J, Evrard S, Khatib AM. Proprotein convertases: Key players in inflammation-related malignancies and metastasis. Cancer Lett. 2020;473:50–61. - PubMed
  101. Mbikay M, Sirois F, Yao J, Seidah NG, Chrétien M. Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. Br J Cancer. 1997;75:1509–14. - PubMed
  102. Cheng M, Watson PH, Paterson JA, Seidah N, Chrétien M, Shiu RPC. Pro-protein convertase gene expression in human breast cancer. Int J Cancer. 1997;71:966–71. - PubMed
  103. Huo X, Zhou X, Peng P, Yu M, Zhang Y, Yang J, et al. Identification of a six-gene signature for predicting the overall survival of cervical cancer patients. Onco Targets Ther. 2021;14:809–22. - PubMed
  104. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–W560. - PubMed
  105. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer Genomics Portal: An open platform for exploring multidimensional cancer genomics data. Cancer Disco. 2012;2:401–4. - PubMed
  106. Ghisoli M, Barve M, Mennel R, Lenarsky C, Horvath S, Wallraven G, et al. Three-year follow up of GMCSF/bi-shRNA(furin) DNA-transfected autologous tumor immunotherapy (Vigil) in metastatic advanced Ewing’s sarcoma. Mol Ther. 2016;24:1478–83. - PubMed
  107. Lei RX, Shi H, Peng XM, Zhu YH, Cheng J, Chen GH. Influence of a single nucleotide polymorphism in the P1 promoter of the furin gene on transcription activity and hepatitis B virus infection. Hepatology. 2009;50:763–71. - PubMed
  108. Turpeinen H, Raitoharju E, Oksanen A, Oksala N, Levula M, Lyytikäinen L-P, et al. Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL. Atherosclerosis. 2011;219:799–806. - PubMed
  109. Declercq J, Jacobs B, Biesmans B, Roth A, Klingbiel D, Tejpar S, et al. Single nucleotide polymorphism (rs4932178) in the P1 promoter of FURIN is not prognostic to colon cancer. Biomed Res Int. 2015;2015:321276. - PubMed
  110. Sarkar FH, Adsule S, Li Y, Padhye S. Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem. 2007;7:599–608. - PubMed
  111. Neel J-C, Humbert L, Lebrun J-J. The dual role of TGFβ in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol. 2012;2012:1–28. - PubMed
  112. Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S, Kurth E, et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene. 2016;35:6077–86. - PubMed
  113. Lowell S, Jones P, Le Roux I, Dunne J, Watt FM. Stimulation of human epidermal differentiation by Delta-Notch signalling at the boundaries of stem-cell clusters. Curr Biol. 2000;10:491–500. - PubMed
  114. Westhoff B, Colaluca IN, D’Ario G, Donzelli M, Tosoni D, Volorio S, et al. Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci USA. 2009;106:22293–8. - PubMed
  115. Baumgart A, Mazur PK, Anton M, Rudelius M, Schwamborn K, Feuchtinger A, et al. Opposing role of Notch1 and Notch2 in a Kras G12D -driven murine non-small cell lung cancer model. Oncogene. 2015;34:578–88. - PubMed
  116. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-∅ from cells. Nature. 1997;385:729–33. - PubMed
  117. Srour N, Lebel A, McMahon S, Fournier I, Fugère M, Day R, et al. TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity. FEBS Lett. 2003;554:275–83. - PubMed
  118. Chang LY, Lin YC, Chiang JM, Mahalingam J, Su SH, Huang CT, et al. Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion. Oncoimmunology. 2015;4:e1040215. - PubMed
  119. Zhao XX, Rong L, Zhao XX, Li X, Liu X, Deng J, et al. TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest. 2012;122:4094–104. - PubMed
  120. Bertrand F, Rochotte J, Colacios C, Montfort A, Tilkin-Mariamé AF, Touriol C, et al. Blocking tumor necrosis factor α enhances CD8 T-cell-dependent immunity in experimental melanoma. Cancer Res. 2015;75:2619–28. - PubMed
  121. Hartley G, Regan D, Guth A, Dow S. Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α. Cancer Immunol Immunother. 2017;66:523–35. - PubMed
  122. Kearney CJ, Vervoort SJ, Hogg SJ, Ramsbottom KM, Freeman AJ, Lalaoui N, et al. Tumor immune evasion arises through loss of TNF sensitivity. Sci Immunol. 2018;3:1–15. - PubMed
  123. Garancher A, Suzuki H, Haricharan S, Chau LQ, Masihi MB, Rusert JM, et al. Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma. Nat Neurosci. 2020;23:842–53. - PubMed
  124. Sarac MS, Cameron A, Lindberg I. The furin inhibitor hexa-D-arginine blocks the activation of Pseudomonas aeruginosa exotoxin a in vivo. Infect Immun. 2002;70:7136–9. - PubMed
  125. Yakala GK, Cabrera-Fuentes HA, Crespo-Avilan GE, Rattanasopa C, Burlacu A, George BL, et al. FURIN inhibition reduces vascular remodeling and atherosclerotic lesion progression in mice. Arterioscler Thromb Vasc Biol. 2019;39:387–401. - PubMed
  126. Senzer N, Barve M, Kuhn J, Melnyk A, Beitsch P, Lazar M, et al. Phase i trial of bi-shRNAi furin/GMCSF DNA/autologous tumor cell vaccine (FANG) in advanced cancer. Mol Ther. 2012;20:679–86. - PubMed
  127. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554:538–43. - PubMed
  128. Oh J, Barve M, Matthews CM, Koon EC, Heffernan TP, Fine B, et al. Phase II study of Vigil® DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer. Gynecol Oncol. 2016;143:504–10. - PubMed
  129. Ghisoli M, Rutledge M, Stephens PJ, Mennel R, Barve M, Manley M, et al. Case report: immune-mediated complete response in a patient with recurrent advanced ewing sarcoma (EWS) After Vigil Immunotherapy. J Pediatr Hematol Oncol. 2017;39:e183–e186. - PubMed
  130. Zhu J, Declercq J, Roucourt B, Ghassabeh GH, Meulemans S, Kinne J, et al. Generation and characterization of non-competitive furin-inhibiting nanobodies. Biochem J. 2012;448:73–82. - PubMed
  131. Couture F, Kwiatkowska A, Dory YL, Day R. Therapeutic uses of furin and its inhibitors: a patent review. Expert Opin Ther Pat. 2015;25:379–96. - PubMed
  132. Klein-Szanto AJ, Bassi DE. Proprotein convertase inhibition: paralyzing the cell’s master switches. Biochem Pharm. 2017;140:8–15. - PubMed
  133. Levesque C, Fugère M, Kwiatkowska A, Couture F, Desjardins R, Routhier S, et al. The multi-leu peptide inhibitor discriminates between pace4 and furin and exhibits antiproliferative effects on prostate cancer cells. J Med Chem. 2012;55:10501–11. - PubMed
  134. Bassi DE, Zhang J, Renner C, Klein-Szanto AJ. Targeting proprotein convertases in furin-rich lung cancer cells results in decreased in vitro and in vivo growth. Mol Carcinog. 2017;56:1182–8. - PubMed
  135. D’Anjou F, Routhier S, Perreault JP, Latil A, Bonnel D, Fournier I, et al. Molecular validation of pace4 as a target in prostate cancer. Transl Oncol. 2011;4:157–72. - PubMed
  136. Maret D, Sadr MS, Sadr ES, Colman DR, Del Maestro RF, Seidah NG. Opposite roles of Furin and PC5A in N-cadherin processing. Neoplasia. 2012;14:880–92. - PubMed
  137. Zhong M, Munzer JS, Basak A, Benjannet S, Mowla SJ, Decroly E, et al. The prosegments of furin and PC7 as potent inhibitors of proprotein convertases. In vitro and ex vivo assessment of their efficacy and selectivity. J Biol Chem. 1999;274:33913–20. - PubMed
  138. Zhou B, Gao S. Pan-cancer analysis of FURIN as a potential prognostic and immunological biomarker. Front Mol Biosci. 2021;8:1–15. - PubMed
  139. Zhao X, Subramanian S. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Res. 2017;77:817–22. - PubMed
  140. Brouwers B, Coppola I, Vints K, Dislich B, Jouvet N, Van Lommel L, et al. Loss of Furin in β-cells induces an mTORC1-ATF4 anabolic pathway that leads to β-cell dysfunction. Diabetes. 2021;70:492–503. - PubMed
  141. Al Rifai O, Susan-Resiga D, Essalmani R, Creemers JWM, Seidah NG, Ferron M. In vivo analysis of the contribution of proprotein convertases to the processing of FGF23. Front Endocrinol (Lausanne). 2021;12:1–13. - PubMed
  142. Jin W, Fuki IV, Seidah NG, Benjannet S, Glick JM, Rader DJ. Proprotein covertases are responsible for proteolysis and inactivation of endothelial lipase. J Biol Chem. 2005;280:36551–9. - PubMed
  143. Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C, et al. In vivo evidence that furin from hepatocytes inactivates PCSK9. J Biol Chem. 2011;286:4257–63. - PubMed
  144. Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580–5. - PubMed
  145. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13. - PubMed

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