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Cited by 43NF-κB Signaling PathwaysTGF-β signaling in diseasesProtease and Inhibitor Mechanisms

Autocrine IL-1β-TRAF6 signalling promotes squamous cell carcinoma invasion through paracrine TNFα signalling to carcinoma-associated fibroblasts

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Chaudhry, S I, Hooper, S, Nye, E, Williamson, P, Harrington, K, Sahai, E·2013·Oncogene
DOI 10.1038/onc.2012.91PMC PMC3446864
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Abstract

The invasion of squamous cell carcinoma (SCC) is a significant cause of morbidity and mortality. Here, we identify an E3 ligase, Traf6 and a de-ubiquitinating enzyme, Cezanne/ZA20D1, as important regulators of this process in organotypic models. Traf6 can promote the formation of Cdc42-dependent F-actin microspikes. Furthermore, Traf6 has a key role in autocrine interleukin-1β signalling in SCC cells, which in turn is required to drive the expression of tumour necrosis factor α (TNFα). TNFα acts in a paracrine manner to increase the invasion-promoting potential of carcinoma-associated fibroblasts (CAFs). Exogenous TNFα signalling can restore invasion in cells depleted of Traf6. In conclusion, Traf6 has two important roles in SCC invasion: it promotes cell intrinsic Cdc42-dependent regulation of the actin cytoskeleton and enables production of the paracrine signal, TNFα, that enhances the activity of CAFs.

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  • The tumour-promoting immunosuppressive activity of FAP+ fibroblasts is associated with suppression of TNF signalling, yet TNF is also able to drive fibroblast activation in certain contexts.

    “However, the situation with tumour necrosis factor (TNF) produced by CAFs is more nuanced; the tumour-promoting immunosuppressive activity of FAP+ fibroblasts is associated with suppression of TNF signalling, yet TNF is also able to drive fibroblast activation in certain contexts16,124,125.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [124]

    The Results section ('TNFα promotes Carcinoma-Associated Fibroblast function') shows that TNFα from squamous carcinoma cells enhances CAF matrix remodelling and invasion-promoting activity, supporting the point that TNF can drive fibroblast activity in this context. The paper does not address immunosuppression by FAP+ fibroblasts or its association with suppressed TNF signalling. It also identifies the cancer cells, not CAFs, as the significant source of TNFα in its model. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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Research works printed but not linked: 39

  1. [1]Gil Z Fliss DM Contemporary management of head and neck cancers Isr Med Assoc J 5 2009 11 5 296 300 19637508
  2. [2]Shah JP Gil Z Current concepts in management of oral cancer--surgery Oral Oncol Apr-May 2009 45 4-5 394 401 18674952 PMC4130348
  3. [3]Yao M Epstein JB Modi BJ Pytynia KB Mundt AJ Feldman LE Current surgical treatment of squamous cell carcinoma of the head and neck Oral Oncol 3 2007 43 3 213 223 16978911
  4. [6]Kalluri R Zeisberg M Fibroblasts in cancer Nat Rev Cancer 5 2006 6 5 392 401 16572188
  5. [7]Olive KP Jacobetz MA Davidson CJ Gopinathan A McIntyre D Honess D Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer Science 12 6 2009 324 5933 1457 1461 19460966 PMC2998180
  6. [8]Erez N Truitt M Olson P Arron ST Hanahan D Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner Cancer Cell 17 2 2010 17 2 135 147 20138012
  7. [9]Sanz-Moreno V Gaggioli C E. ROCK and JAK1 signalling cooperate to control actomyosin contractility in tumour cells and stroma Cancer Cell al. in press 21840487
  8. [10]Stuelten CH DaCosta Byfield S Arany PR Karpova TS Stetler-Stevenson WG Roberts AB Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-alpha and TGF-beta J Cell Sci 15 5 2005 118 Pt 10 2143 2153 15855236
  9. [11]Wajant H Henkler F Scheurich P The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators Cell Signal 6 2001 13 6 389 400 11384837
  10. [12]Deng L Wang C Spencer E Yang L Braun A You J Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain Cell 13 10 2000 103 2 351 361 11057907
  11. [14]Wojciak-Stothard B Entwistle A Garg R Ridley AJ Regulation of TNF-alpha-induced reorganization of the actin cytoskeleton and cell-cell junctions by Rho, Rac, and Cdc42 in human endothelial cells J Cell Physiol 7 1998 176 1 150 165 9618155
  12. [15]Pritchard S Guilak F Effects of interleukin-1 on calcium signaling and the increase of filamentous actin in isolated and in situ articular chondrocytes Arthritis Rheum 7 2006 54 7 2164 2174 16802354
  13. [16]Ridley AJ Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking Trends Cell Biol 10 2006 16 10 522 529 16949823
  14. [17]Wang HR Zhang Y Ozdamar B Ogunjimi AA Alexandrova E Thomsen GH Regulation of cell polarity and protrusion formation by targeting RhoA for degradation Science 5 12 2003 302 5651 1775 1779 14657501
  15. [18]Chen Y Yang Z Meng M Zhao Y Dong N Yan H Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement Mol Cell 24 9 2009 35 6 841 855 19782033
  16. [19]Castillo-Lluva S Tatham MH Jones RC Jaffray EG Edmondson RD Hay RT SUMOylation of the GTPase Rac1 is required for optimal cell migration Nat Cell Biol 11 2010 12 11 1078 1085 2010 20935639 PMC2992316
  17. [20]Evans PC Smith TS Lai MJ Williams MG Burke DF Heyninck K A novel type of deubiquitinating enzyme J Biol Chem 20 6 2003 278 25 23180 23186 12682062
  18. [21]Evans PC Taylor ER Coadwell J Heyninck K Beyaert R Kilshaw PJ Isolation and characterization of two novel A20-like proteins Biochem J 1 8 2001 357 Pt 3 617 623 11463333 PMC1221992
  19. [22]Wang KZ Wara-Aswapati N Boch JA Yoshida Y Hu CD Galson DL TRAF6 activation of PI 3-kinase-dependent cytoskeletal changes is cooperative with Ras and is mediated by an interaction with cytoplasmic Src J Cell Sci 15 4 2006 119 Pt 8 1579 1591 16569657
  20. [23]Yang WL Wang J Chan CH Lee SW Campos AD Lamothe B The E3 ligase TRAF6 regulates Akt ubiquitination and activation Science 28 8 2009 325 5944 1134 1138 19713527 PMC3008763
  21. [24]Nystrom ML Thomas GJ Stone M Mackenzie IC Hart IR Marshall JF Development of a quantitative method to analyse tumour cell invasion in organotypic culture J Pathol 3 2005 205 4 468 475 15685705
  22. [25]Ahn KS Sethi G Aggarwal BB Nuclear factor-kappa B: from clone to clinic Curr Mol Med 11 2007 7 7 619 637 18045141
  23. [26]Windheim M Stafford M Peggie M Cohen P Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase Mol Cell Biol 3 2008 28 5 1783 1791 18180283 PMC2258775
  24. [27]Yin Q Lin SC Lamothe B Lu M Lo YC Hura G E2 interaction and dimerization in the crystal structure of TRAF6 Nat Struct Mol Biol 6 2009 16 6 658 666 19465916 PMC2834951
  25. [28]Enesa K Zakkar M Chaudhury H Luong le A Rawlinson L Mason JC NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling J Biol Chem 14 3 2008 283 11 7036 7045 18178551
  26. [29]Bremm A Freund SM Komander D Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne Nat Struct Mol Biol 8 2010 17 8 939 947 20622874 PMC2917782
  27. [30]Tse WK Eisenhaber B Ho SH Ng Q Eisenhaber F Jiang YJ Genome-wide loss-of-function analysis of deubiquitylating enzymes for zebrafish development BMC Genomics 2009 10 637 20040115 PMC2809080
  28. [31]Krelin Y Voronov E Dotan S Elkabets M Reich E Fogel M Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors Cancer Res 1 2 2007 67 3 1062 1071 17283139
  29. [32]Szlosarek PW Balkwill FR Tumour necrosis factor alpha: a potential target for the therapy of solid tumours Lancet Oncol 9 2003 4 9 565 573 12965278
  30. [33]Scott KA Moore RJ Arnott CH East N Thompson RG Scallon BJ An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors Mol Cancer Ther 5 2003 2 5 445 451 12748306
  31. [35]Jeong JG Kim JM Cho H Hahn W Yu SS Kim S Effects of IL-1beta on gene expression in human rheumatoid synovial fibroblasts Biochem Biophys Res Commun 5 11 2004 324 1 3 7 15464974
  32. [36]Hanna AN Berthiaume LG Kikuchi Y Begg D Bourgoin S Brindley DN Tumor necrosis factor-alpha induces stress fiber formation through ceramide production: role of sphingosine kinase Mol Biol Cell 11 2001 12 11 3618 3630 11694593 PMC60280
  33. [37]Gronowicz G Hadjimichael J Richards D Cerami A Rossomando EF Correlation between tumor necrosis factor-alpha (TNF-alpha)-induced cytoskeletal changes and human collagenase gene induction J Periodontal Res 11 1992 27 6 562 568 1334144
  34. [38]Smith PC Guerrero J Tobar N Caceres M Gonzalez MJ Martinez J Tumor necrosis factor-alpha-stimulated membrane type 1-matrix metalloproteinase production is modulated by epidermal growth factor receptor signaling in human gingival fibroblasts J Periodontal Res 2 2009 44 1 73 80 19515020
  35. [39]Elmets CA Viner JL Pentland AP Cantrell W Lin HY Bailey H Chemoprevention of nonmelanoma skin cancer with celecoxib: a randomized, double-blind, placebo-controlled trial J Natl Cancer Inst 15 12 2010 102 24 1835 1844 21115882 PMC3001966
  36. [40]Kurihara Y Hatori M Ando Y Ito D Toyoshima T Tanaka M Inhibition of cyclooxygenase-2 suppresses the invasiveness of oral squamous cell carcinoma cell lines via down-regulation of matrix metalloproteinase-2 production and activation Clin Exp Metastasis 2009 26 5 425 432 19241124
  37. [41]Rosenblum H Amital H Anti-TNF therapy: safety aspects of taking the risk Autoimmun Rev 7 2011 10 9 563 568 21570495
  38. [42]Hidalgo-Carcedo C Hooper S Chaudhry SI Williamson P Harrington K Leitinger B Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6 Nat Cell Biol 1 2011 13 1 49 58 21170030 PMC3018349
  39. [43]Hooper S Gaggioli C Sahai E A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion Br J Cancer 19 1 102 2 392 402 19953096 PMC2816649

Cited by

Sorted by citations

Authors
Chaudhry, S. I., Hooper, S., Nye, E., Williamson, P., Harrington, K., & Sahai, E.
Affiliations
  • Cancer Research UK (GB)
  • St George's Hospital (GB)
  • Institute of Cancer Research (GB)
Corresponding author
Sahai, E
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2012-03-26
Volume
32
Issue
6
Pages
747-758
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2012.91
PMC
PMC3446864
OpenAlex
W2010885105
Cited by
43
References
5
Citations by year
2025: 5 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 7 · 2012: 2
FWCI
1.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
Cancer Research UK (15154, A5317)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
squamous cell carcinoma, tumor invasion, TRAF6, E3 ubiquitin ligase, deubiquitinase, autocrine signaling, paracrine signaling, TNF-α, cancer-associated fibroblasts, Cdc42, actin cytoskeleton, organotypic models
MeSH terms
Carcinoma, Squamous Cell, Fibroblasts, Humans, Neoplasm Invasiveness, Endopeptidases, Tumor Necrosis Factor-alpha, Signal Transduction, Autocrine Communication, Paracrine Communication, cdc42 GTP-Binding Protein, TNF Receptor-Associated Factor 6, Interleukin-1beta

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