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Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

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Abstract

Purpose

Transglutaminases (TGs) are multifunctional enzymes exhibiting transglutaminase crosslinking, as well as atypical GTPase/ATPase and kinase activities. Here, we used an integrated comprehensive analysis to assess the genomic, transcriptomic and immunological landscapes of TGs across cancers.

Methods

Gene expression and immune cell infiltration patterns across cancers were obtained from The Cancer Genome Atlas (TCGA) database and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assays, and orthotopic xenograft models were used to validate our database-derived results.

Results

We found that the overall expression of TGs (designated as the TG score) is significantly upregulated in multiple cancers and related to a worse patient survival. The expression of TG family members can be regulated through multiple mechanisms at the genetic, epigenetic and transcriptional levels. The expression of transcription factors crucial for epithelial-to-mesenchymal transition (EMT) is commonly correlated with the TG score in many cancer types. Importantly, TGM2 expression displays a close connection with chemoresistance to a wide range of chemotherapeutic drugs. We found that TGM2 expression, F13A1 expression and the overall TG score were positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification revealed that a higher TGM2 expression is linked with a worse patient survival, an increased IC50 value of gemcitabine, and a higher abundance of tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, we found that increased C–C motif chemokine ligand 2 (CCL2) release mediated by TGM2 contributes to macrophage infiltration into the tumor microenvironment.

Conclusions

Our results reveal the relevance and molecular networks of TG genes in human cancers and highlight the importance of TGM2 in pancreatic cancer, which may provide promising directions for immunotherapy and for addressing chemoresistance.

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Data availability

All sequencing data were obtained from publicly available database (TCGA https://portal.gdc.cancer.gov and GTEx https://xenabrowser.net) and other data generated or analyzed in this study were included in the article.

References

  1. E.S. Chermnykh, E.V. Alpeeva, E.A. Vorotelyak, Transglutaminase 3: the involvement in epithelial differentiation and cancer. Cells 9, 1996 (2020)

  2. J.E. Folk, P.W. Cole, Identification of a functional cysteine essential for the activity of guinea pig liver transglutaminase. J. Biol. Chem. 241, 3238–3240 (1966)

    CAS  PubMed  Google Scholar 

  3. S.E. Iismaa, S. Holman, M.A. Wouters, L. Lorand, R.M. Graham, A. Husain, Evolutionary specialization of a tryptophan indole group for transition-state stabilization by eukaryotic transglutaminases. Proc. Natl. Acad. Sci. U. S. A. 100, 12636–12641 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. K.N. Lee, S.A. Arnold, P.J. Birckbichler, M.K. Patterson Jr., B.M. Fraij, Y. Takeuchi, H.A. Carter, Site-directed mutagenesis of human tissue transglutaminase: Cys-277 is essential for transglutaminase activity but not for GTPase activity. Biochim. Biophys. Acta 1202, 1–6 (1993)

    CAS  PubMed  Google Scholar 

  5. R. Micanovic, R. Procyk, W. Lin, G.R. Matsueda, Role of histidine 373 in the catalytic activity of coagulation factor XIII. J. Biol. Chem 269, 9190–9194 (1994)

    CAS  PubMed  Google Scholar 

  6. S.N. Murthy, S. Iismaa, G. Begg, D.M. Freymann, R.M. Graham, L. Lorand, Conserved tryptophan in the core domain of transglutaminase is essential for catalytic activity. Proc. Natl. Acad. Sci. U. S. A. 99, 2738–2742 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. L.C. Pedersen, V.C. Yee, P.D. Bishop, I. Le Trong, D.C. Teller, R.E. Stenkamp, Transglutaminase factor XIII uses proteinase-like catalytic triad to crosslink macromolecules. Protein Sci. 3, 1131–1135 (1994)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. S.Y. Kim, T.M. Jeitner, P.M. Steinert, Transglutaminases in disease. Neurochem. Int. 40, 85–103 (2002)

    CAS  PubMed  Google Scholar 

  9. G. Hasegawa, M. Suwa, Y. Ichikawa, T. Ohtsuka, S. Kumagai, M. Kikuchi, Y. Sato, Y. Saito, A novel function of tissue-type transglutaminase: protein disulphide isomerase. Biochem. J. 373, 793–803 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. S.E. Iismaa, B.M. Mearns, L. Lorand, R.M. Graham, Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol. Rev. 89, 991–1023 (2009)

    CAS  PubMed  Google Scholar 

  11. S. Mishra, L.J. Murphy, Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase. J. Biol. Chem. 279, 23863–23868 (2004)

    CAS  PubMed  Google Scholar 

  12. L. Muszbek, R. Adány, M. Kávai, Z. Boda, S. Lopaciuk, Monocytes of patients congenitally deficient in plasma factor XIII lack factor XIII subunit a antigen and transglutaminase activity. Thromb. Haemost. 59, 231–235 (1988)

    CAS  PubMed  Google Scholar 

  13. L. Lorand, N. Barnes, J.A. Bruner-Lorand, M. Hawkins, M. Michalska, Inhibition of protein cross-linking in Ca2+-enriched human erythrocytes and activated platelets. Biochemistry 26, 308–313 (1987)

    CAS  PubMed  Google Scholar 

  14. L. Lorand, Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann. N. Y. Acad. Sci. 936, 291–311 (2001)

    CAS  PubMed  Google Scholar 

  15. H.C. Kim, Z. Nemes, W.W. Idler, C.C. Hyde, P.M. Steinert, B. Ahvazi, Crystallization and preliminary X-ray analysis of human transglutaminase 3 from zymogen to active form. J. Struct. Biol. 135, 73–77 (2001)

    CAS  PubMed  Google Scholar 

  16. Z. Nemes, L.N. Marekov, L. Fésüs, P.M. Steinert, A novel function for transglutaminase 1: attachment of long-chain omega-hydroxyceramides to involucrin by ester bond formation. Proc. Natl. Acad. Sci. U. S. A. 96, 8402–8407 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. D. Aeschlimann, O. Kaupp, M. Paulsson, Transglutaminase-catalyzed matrix cross-linking in differentiating cartilage: identification of osteonectin as a major glutaminyl substrate. J. Cell. Biol. 129, 881–892 (1995)

    CAS  PubMed  Google Scholar 

  18. M. Wozniak, A. Fausto, C.P. Carron, D.M. Meyer, K.A. Hruska, Mechanically strained cells of the osteoblast lineage organize their extracellular matrix through unique sites of alphavbeta3-integrin expression. J. Bone Miner. Res. 15, 1731–1745 (2000)

    CAS  PubMed  Google Scholar 

  19. H. Mikkola, V.C. Yee, M. Syrjälä, R. Seitz, R. Egbring, P. Petrini, R. Ljung, J. Ingerslev, D.C. Teller, L. Peltonen, A. Palotie, Four novel mutations in deficiency of coagulation factor XIII: consequences to expression and structure of the A-subunit. Blood 87, 141–151 (1996)

    CAS  PubMed  Google Scholar 

  20. M. Huber, I. Rettler, K. Bernasconi, E. Frenk, S.P. Lavrijsen, M. Ponec, A. Bon, S. Lautenschlager, D.F. Schorderet, D. Hohl, Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science 267, 525–528 (1995)

    CAS  PubMed  Google Scholar 

  21. Z. Nemes, M. Demény, L.N. Marekov, L. Fésüs, P.M. Steinert, Cholesterol 3-sulfate interferes with cornified envelope assembly by diverting transglutaminase 1 activity from the formation of cross-links and esters to the hydrolysis of glutamine. J. Biol. Chem. 275, 2636–2646 (2000)

    CAS  PubMed  Google Scholar 

  22. M. Sárdy, S. Kárpáti, B. Merkl, M. Paulsson, N. Smyth, Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J. Exp. Med. 195, 747–757 (2002)

    PubMed  PubMed Central  Google Scholar 

  23. W. Dieterich, T. Ehnis, M. Bauer, P. Donner, U. Volta, E.O. Riecken, D. Schuppan, Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med. 3, 797–801 (1997)

    CAS  PubMed  Google Scholar 

  24. L. Lorand, R.M. Graham, Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat. Rev. Mol. Cell Biol. 4, 140–156 (2003)

    CAS  PubMed  Google Scholar 

  25. H. Huang, Z. Chen, X. Ni, Tissue transglutaminase-1 promotes stemness and chemoresistance in gastric cancer cells by regulating Wnt/β-catenin signaling. Exp. Biol. Med. (Maywood) 242, 194–202 (2017)

    CAS  PubMed  Google Scholar 

  26. J.W. Hu, Z.F. Yang, J. Li, B. Hu, C.B. Luo, K. Zhu, Z. Dai, J.B. Cai, H. Zhan, Z.Q. Hu, J. Hu, Y. Cao, S.J. Qiu, J. Zhou, J. Fan, X.W. Huang, TGM3 promotes epithelial-mesenchymal transition and hepatocellular carcinogenesis and predicts poor prognosis for patients after curative resection. Dig. Liver Dis. 52, 668–676 (2020)

    CAS  PubMed  Google Scholar 

  27. E. Méndez, W. Fan, P. Choi, S.N. Agoff, M. Whipple, D.G. Farwell, N.D. Futran, E.A. Weymuller Jr., L.P. Zhao, C. Chen, Tumor-specific genetic expression profile of metastatic oral squamous cell carcinoma. Head Neck 29, 803–814 (2007)

    PubMed  Google Scholar 

  28. A. Negishi, M. Masuda, M. Ono, K. Honda, M. Shitashige, R. Satow, T. Sakuma, H. Kuwabara, Y. Nakanishi, Y. Kanai, K. Omura, S. Hirohashi, T. Yamada, Quantitative proteomics using formalin-fixed paraffin-embedded tissues of oral squamous cell carcinoma. Cancer Sci. 100, 1605–1611 (2009)

    CAS  PubMed  Google Scholar 

  29. J. Liu, Y. Zhou, J. Wan, Z. Liu, Expression of TGM3 protein and its significance in laryngeal carcinoma. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 26, 101–103 (2012)

    Google Scholar 

  30. B.S. Chen, M.R. Wang, X. Xu, Y. Cai, Z.X. Xu, Y.L. Han, M. Wu, Transglutaminase-3, an esophageal cancer-related gene. Int. J. Cancer 88, 862–865 (2000)

    CAS  PubMed  Google Scholar 

  31. A. Smirnov, L. Anemona, M. Montanaro, A. Mauriello, M. Annicchiarico-Petruzzelli, E. Campione, G. Melino, E. Candi, Transglutaminase 3 is expressed in basal cell carcinoma of the skin. Eur. J. Dermatol. 29, 477–483 (2019)

    CAS  PubMed  Google Scholar 

  32. Z. Cao, Y. Wang, Z.Y. Liu, Z.S. Zhang, S.C. Ren, Y.W. Yu, M. Qiao, B.B. Zhai, Y.H. Sun, Overexpression of transglutaminase 4 and prostate cancer progression: a potential predictor of less favourable outcomes. Asian J. Androl. 15, 742–746 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Y. Zhou, Y. Zang, Y. Yang, J. Xiang, Z. Chen, Candidate genes involved in metastasis of colon cancer identified by integrated analysis. Cancer Med. 8, 2338–2347 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. M. Meng, S. Liu, C. Wang, X. Gu, E. Linghu, X. Xue, Mass spectrum analysis of membrane proteins reveals that CASK, CD36 and EPB42 are differentially expressed in pancreatic adenocarcinoma. Oncol. Lett. 20, 376 (2020)

    PubMed  PubMed Central  Google Scholar 

  35. J. Peltier, J.P. Roperch, S. Audebert, J.P. Borg, L. Camoin, Activation peptide of the coagulation factor XIII (AP-F13A1) as a new biomarker for the screening of colorectal cancer. Clin. Proteomics 15, 15 (2018)

    PubMed  PubMed Central  Google Scholar 

  36. Cancer Genome Atlas Research Network. Electronic address: andrew_aguirre@dfci.harvard.edu; Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203.e13 (2017)

  37. P. Charoentong, F. Finotello, M. Angelova, C. Mayer, M. Efremova, D. Rieder, H. Hackl, Z. Trajanoski, Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 18, 248–262 (2017)

    CAS  PubMed  Google Scholar 

  38. S.H. Jiang, J. Li, F.Y. Dong, J.Y. Yang, D.J. Liu, X.M. Yang, Y.H. Wang, M.W. Yang, X.L. Fu, X.X. Zhang, Q. Li, X.F. Pang, Y.M. Huo, J. Li, J.F. Zhang, H.Y. Lee, S.J. Lee, W.X. Qin, J.R. Gu, Y.W. Sun, Z.G. Zhang, Increased serotonin signaling contributes to the Warburg effect in pancreatic tumor cells under metabolic stress and promotes growth of pancreatic tumors in mice. Gastroenterology 153, 277-291.e19 (2017)

    CAS  PubMed  Google Scholar 

  39. Q. Li, X.X. Zhang, L.P. Hu, B. Ni, D.X. Li, X. Wang, S.H. Jiang, H. Li, M.W. Yang, Y.S. Jiang, C.J. Xu, X.L. Zhang, Y.L. Zhang, P.Q. Huang, Q. Yang, Y. Zhou, J.R. Gu, G.G. Xiao, Y.W. Sun, J. Li, Z.G. Zhang, Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma. Nat. Commun. 14, 861 (2023)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. M. Pigors, D. Kiritsi, C. Cobzaru, A. Schwieger-Briel, J. Suárez, F. Faletra, H. Aho, L. Mäkelä, J.S. Kern, L. Bruckner-Tuderman, C. Has, TGM5 mutations impact epidermal differentiation in acral peeling skin syndrome. J. Invest. Dermatol. 132, 2422–2429 (2012)

    CAS  PubMed  Google Scholar 

  41. K. Chen, Y. Lu, F. Peng, H.L. Yu, J.Y. Wu, Y. Tan, Y.X. Zhao, TGM6 variants in Parkinson’s disease: clinical findings and functional evidence. J. Integr. Neurosci. 19, 51–64 (2020)

    PubMed  Google Scholar 

  42. A. Schulze-Krebs, F. Canneva, J. Stemick, A.C. Plank, J. Harrer, G.P. Bates, D. Aeschlimann, J.S. Steffan, S. von Hörsten, Transglutaminase 6 is colocalized and interacts with mutant huntingtin in Huntington disease rodent animal models. Int. J. Mol. Sci. 22, 8914 (2021)

  43. N.V. Serbina, E.G. Pamer, Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006)

    CAS  PubMed  Google Scholar 

  44. Y. Ding, V. Labitzky, K. Legler, M. Qi, U. Schumacher, B. Schmalfeldt, C. Stürken, L. Oliveira-Ferrer, Molecular characteristics and tumorigenicity of ascites-derived tumor cells: mitochondrial oxidative phosphorylation as a novel therapy target in ovarian cancer. Mol. Oncol. 15, 3578–3595 (2021)

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Y. Luo, B. Li, J. Li, Y. Zhang, M. Deng, C. Hu, W. Yan, Z. Zhou, G. Zhang, Coagulation factor XIII Subunit A Is a biomarker for curative effects and prognosis in malignant solid tumors, especially non-small cell lung cancer. Front. Oncol. 11, 719085 (2021)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Y. Sawai, Y. Yamanaka, S. Nomura, Clinical significance of factor XIII activity and monocyte-derived microparticles in cancer patients. Vasc. Health Risk Manag. 16, 103–110 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  47. A. Porrello, P.L. Leslie, E.B. Harrison, B.K. Gorentla, S. Kattula, S.K. Ghosh, S.H. Azam, A. Holtzhausen, Y.L. Chao, M.C. Hayward, T.A. Waugh, S. Bae, V. Godfrey, S.H. Randell, C. Oderup, L. Makowski, J. Weiss, M.D. Wilkerson, D.N. Hayes, H.S. Earp, A.S. Baldwin, A.S. Wolberg, C.V. Pecot, Factor XIIIA-expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking. Nat. Commun. 9, 1988 (2018)

    PubMed  PubMed Central  Google Scholar 

  48. J.S. Palumbo, K.A. Barney, E.A. Blevins, M.A. Shaw, A. Mishra, M.J. Flick, K.W. Kombrinck, K.E. Talmage, M. Souri, A. Ichinose, J.L. Degen, Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function. J. Thromb. Haemost. 6, 812–819 (2008)

    CAS  PubMed  Google Scholar 

  49. H. Nakaoka, D.M. Perez, K.J. Baek, T. Das, A. Husain, K. Misono, M.J. Im, R.M. Graham, Gh: a GTP-binding protein with transglutaminase activity and receptor signaling function. Science 264, 1593–1596 (1994)

    CAS  PubMed  Google Scholar 

  50. G.E. Begg, L. Carrington, P.H. Stokes, J.M. Matthews, M.A. Wouters, A. Husain, L. Lorand, S.E. Iismaa, R.M. Graham, Mechanism of allosteric regulation of transglutaminase 2 by GTP. Proc. Natl. Acad. Sci. U. S. A. 103, 19683–19688 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  51. D. Aeschlimann, M. Paulsson, K. Mann, Identification of Gln726 in nidogen as the amine acceptor in transglutaminase-catalyzed cross-linking of laminin-nidogen complexes. J. Biol. Chem. 267, 11316–11321 (1992)

    CAS  PubMed  Google Scholar 

  52. M.T. Kaartinen, A. Pirhonen, A. Linnala-Kankkunen, P.H. Mäenpää, Transglutaminase-catalyzed cross-linking of osteopontin is inhibited by osteocalcin. J. Biol. Chem. 272, 22736–22741 (1997)

    CAS  PubMed  Google Scholar 

  53. C.S. Greenberg, P.J. Birckbichler, R.H. Rice, Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J. 5, 3071–3077 (1991)

    CAS  PubMed  Google Scholar 

  54. S.H. Jiang, Y.H. Wang, L.P. Hu, X. Wang, J. Li, X.L. Zhang, Z.G. Zhang, The physiology, pathology and potential therapeutic application of serotonylation. J. Cell Sci. 134, 257337 (2021)

  55. D. Telci, M. Griffin, Tissue transglutaminase (TG2)–a wound response enzyme. Front. Biosci. 11, 867–882 (2006)

    CAS  PubMed  Google Scholar 

  56. S. Oliverio, A. Amendola, C. Rodolfo, A. Spinedi, M. Piacentini, Inhibition of “tissue” transglutaminase increases cell survival by preventing apoptosis. J. Biol. Chem. 274, 34123–34128 (1999)

    CAS  PubMed  Google Scholar 

  57. A. Chhabra, A. Verma, K. Mehta, Tissue transglutaminase promotes or suppresses tumors depending on cell context. Anticancer Res. 29, 1909–1919 (2009)

    CAS  PubMed  Google Scholar 

  58. M.A. Antonyak, J.M. Jansen, A.M. Miller, T.K. Ly, M. Endo, R.A. Cerione, Two isoforms of tissue transglutaminase mediate opposing cellular fates. Proc. Natl. Acad. Sci. U. S. A. 103, 18609–18614 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  59. J. Sebat, B. Lakshmi, J. Troge, J. Alexander, J. Young, P. Lundin, S. Månér, H. Massa, M. Walker, M. Chi, N. Navin, R. Lucito, J. Healy, J. Hicks, K. Ye, A. Reiner, T.C. Gilliam, B. Trask, N. Patterson, A. Zetterberg, M. Wigler, Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004)

    CAS  PubMed  Google Scholar 

  60. A. Kumar, J. Xu, S. Brady, H. Gao, D. Yu, J. Reuben, K. Mehta, Tissue transglutaminase promotes drug resistance and invasion by inducing mesenchymal transition in mammary epithelial cells. PLoS ONE 5, e13390 (2010)

    PubMed  PubMed Central  Google Scholar 

  61. H. Ma, L. Xie, L. Zhang, X. Yin, H. Jiang, X. Xie, R. Chen, H. Lu, Z. Ren, Activated hepatic stellate cells promote epithelial-to-mesenchymal transition in hepatocellular carcinoma through transglutaminase 2-induced pseudohypoxia. Commun. Biol. 1, 168 (2018)

    PubMed Central  Google Scholar 

  62. M. Shao, L. Cao, C. Shen, M. Satpathy, B. Chelladurai, R.M. Bigsby, H. Nakshatri, D. Matei, Epithelial-to-mesenchymal transition and ovarian tumor progression induced by tissue transglutaminase. Cancer Res. 69, 9192–9201 (2009)

    CAS  PubMed  Google Scholar 

  63. Y. Feng, D. Ji, Y. Huang, B. Ji, Y. Zhang, J. Li, W. Peng, C. Zhang, D. Zhang, Y. Sun, Z. Xu, TGM3 functions as a tumor suppressor by repressing epithelial-to-mesenchymal transition and the PI3K/AKT signaling pathway in colorectal cancer. Oncol. Rep. 43, 864–876 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  64. S.J. Grille, A. Bellacosa, J. Upson, A.J. Klein-Szanto, F. van Roy, W. Lee-Kwon, M. Donowitz, P.N. Tsichlis, L. Larue, The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 63, 2172–2178 (2003)

    CAS  PubMed  Google Scholar 

  65. Q. Zhao, Y. Ren, H. Xie, L. Yu, J. Lu, W. Jiang, W. Xiao, Z. Zhu, R. Wan, B. Li, ELK3 mediated by ZEB1 facilitates the growth and metastasis of pancreatic carcinoma by activating the Wnt/β-Catenin pathway. Front. Cell Dev. Biol. 9, 700192 (2021)

    PubMed  PubMed Central  Google Scholar 

  66. T.Z. Li, S.M. Kim, W. Hur, J.E. Choi, J.H. Kim, S.W. Hong, E.B. Lee, J.H. Lee, S.K. Yoon, Elk-3 contributes to the progression of liver fibrosis by regulating the epithelial-mesenchymal transition. Gut Liver 11, 102–111 (2017)

    CAS  PubMed  Google Scholar 

  67. Y. Chen, T. Wang, M. Huang, Q. Liu, C. Hu, B. Wang, D. Han, C. Chen, J. Zhang, Z. Li, C. Liu, W. Lei, Y. Chang, M. Wu, D. Xiang, Y. Chen, R. Wang, W. Huang, Z. Lei, X. Chu, MAFB promotes cancer stemness and tumorigenesis in osteosarcoma through a Sox9-mediated positive feedback loop. Can. Res. 80, 2472 (2020)

    CAS  Google Scholar 

  68. T. Nemoto, Y. Shibata, S. Inoue, A. Igarashi, Y. Tokairin, K. Yamauchi, T. Kimura, M. Sato, K. Sato, H. Nakano, S. Abe, M. Nishiwaki, M. Kobayashi, S. Yang, Y. Minegishi, K. Furuyama, H. Machida, I. Kubota, MafB silencing in macrophages does not influence the initiation and growth of lung cancer induced by urethane. EXCLI J. 16, 914–920 (2017)

    PubMed  PubMed Central  Google Scholar 

  69. S. Mzoughi, Y.X. Tan, D. Low, E. Guccione, The role of PRDMs in cancer: one family, two sides. Curr. Opin. Genet. Dev. 36, 83–91 (2016)

    CAS  PubMed  Google Scholar 

  70. Y.H. Zhu, J.H. Zheng, Q.Y. Jia, Z.H. Duan, H.F. Yao, J. Yang, Y.W. Sun, S.H. Jiang, D. J. Liu, Y. M. Huo, Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment. Cell Oncol (Dordr) 46, 17–48 (2022)

  71. E.M. Richard, T. Thiyagarajan, M.A. Bunni, F. Basher, P.O. Roddy, L.J. Siskind, P.J. Nietert, T.K. Nowling, Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism. PLoS ONE 8, e75175 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  72. K.P. Sundararaj, T. Thiyagarajan, I. Molano, F. Basher, T.W. Powers, R.R. Drake, T.K. Nowling, FLI1 levels impact CXCR3 expression and renal infiltration of T cells and renal glycosphingolipid metabolism in the MRL/lpr lupus mouse strain. J. Immunol. 195, 5551–5560 (2015)

    CAS  PubMed  Google Scholar 

  73. K. Kim, S.Y. Bang, H.S. Lee, S.K. Cho, C.B. Choi, Y.K. Sung, T.H. Kim, J.B. Jun, D.H. Yoo, Y.M. Kang, S.K. Kim, C.H. Suh, S.C. Shim, S.S. Lee, J. Lee, W.T. Chung, J.Y. Choe, H.D. Shin, J.Y. Lee, B.G. Han, S.K. Nath, S. Eyre, J. Bowes, D.A. Pappas, J.M. Kremer, M.A. Gonzalez-Gay, L. Rodriguez-Rodriguez, L. Ärlestig, Y. Okada, D. Diogo, K.P. Liao, E.W. Karlson, S. Raychaudhuri, S. Rantapää-Dahlqvist, J. Martin, L. Klareskog, L. Padyukov, P.K. Gregersen, J. Worthington, J.D. Greenberg, R.M. Plenge, S.C. Bae, High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. Ann. Rheum. Dis. 74, e13 (2015)

    PubMed  Google Scholar 

  74. S. Bradshaw, W.J. Zheng, L.C. Tsoi, G. Gilkeson, X.K. Zhang, A role for Fli-1 in B cell proliferation: implications for SLE pathogenesis. Clin. Immunol. 129, 19–30 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Y.S. He, X.K. Yang, Y.Q. Hu, K. Xiang, H.F. Pan, Emerging role of Fli1 in autoimmune diseases. Int. Immunopharmacol. 90, 107127 (2021)

    CAS  PubMed  Google Scholar 

  76. Z. Chen, E. Arai, O. Khan, Z. Zhang, S.F. Ngiow, Y. He, H. Huang, S. Manne, Z. Cao, A.E. Baxter, Z. Cai, E. Freilich, M.A. Ali, J.R. Giles, J.E. Wu, A.R. Greenplate, M.A. Hakeem, Q. Chen, M. Kurachi, K. Nzingha, V. Ekshyyan, D. Mathew, Z. Wen, N.A. Speck, A. Battle, S.L. Berger, E.J. Wherry, J. Shi, In vivo CD8(+) T cell CRISPR screening reveals control by Fli1 in infection and cancer. Cell 184, 1262-1280.e22 (2021)

    CAS  PubMed  PubMed Central  Google Scholar 

  77. D.Y. van Haaften-Visser, M. Harakalova, E. Mocholi, J.M. van Montfrans, A. Elkadri, E. Rieter, K. Fiedler, P.M. van Hasselt, E.M.M. Triffaux, M.M. van Haelst, I.J. Nijman, W.P. Kloosterman, E.E.S. Nieuwenhuis, A.M. Muise, E. Cuppen, R.H.J. Houwen, P.J. Coffer, Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease. J. Biol. Chem. 292, 7904–7920 (2017)

    PubMed  PubMed Central  Google Scholar 

  78. O. Küçükşahin, A. Ateş, N. Türkçapar, M. Törüner, M. Turgay, T. Duman, A. Şahin, M.T. Yıldızgören, A.K. Okoh, E. Külahçıoğlu, Ş Erten, G. Kınıklı, S. Assadpour, N. Düzgün, Association between single nucleotide polymorphisms in prospective genes and susceptibility to ankylosing spondylitis and inflammatory bowel disease in a single centre in Turkey. Turk. J. Gastroenterol. 27, 317–324 (2016)

    PubMed  Google Scholar 

  79. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–78 (2007)

  80. X. Du, Y. Zhou, L. Song, X. Wang, S. Zhang, Zinc finger protein 365 is a new maternal LPS-binding protein that defends zebrafish embryos against gram-negative bacterial infections. FASEB J. 32, 979–994 (2018)

    CAS  PubMed  Google Scholar 

  81. T. Bekaii-Saab, M.A. Phelps, X. Li, M. Saji, L. Goff, J.S. Kauh, B.H. O’Neil, S. Balsom, C. Balint, R. Liersemann, V.V. Vasko, M. Bloomston, W. Marsh, L.A. Doyle, G. Ellison, M. Grever, M.D. Ringel, M.A. Villalona-Calero, Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J. Clin. Oncol. 29, 2357–2363 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  82. C.D. Weekes, D.D. Von Hoff, A.A. Adjei, D.P. Leffingwell, S.G. Eckhardt, L. Gore, K.D. Lewis, G.J. Weiss, R.K. Ramanathan, G.K. Dy, W.W. Ma, B. Sheedy, C. Iverson, J.N. Miner, Z. Shen, L.T. Yeh, R.L. Dubowy, M. Jeffers, P. Rajagopalan, N.J. Clendeninn, Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86–9766 in patients with advanced cancer. Clin. Cancer Res. 19, 1232–1243 (2013)

    CAS  PubMed  Google Scholar 

  83. H.Y. Lim, J. Heo, H.J. Choi, C.Y. Lin, J.H. Yoon, C. Hsu, K.M. Rau, R.T. Poon, W. Yeo, J.W. Park, M.H. Tay, W.S. Hsieh, C. Kappeler, P. Rajagopalan, H. Krissel, M. Jeffers, C.J. Yen, W.Y. Tak, A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86–9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin. Cancer Res. 20, 5976–5985 (2014)

    CAS  PubMed  Google Scholar 

  84. R. Schmieder, F. Puehler, R. Neuhaus, M. Kissel, A.A. Adjei, J.N. Miner, D. Mumberg, K. Ziegelbauer, A. Scholz, Allosteric MEK1/2 inhibitor refametinib (BAY 86–9766) in combination with sorafenib exhibits antitumor activity in preclinical murine and rat models of hepatocellular carcinoma. Neoplasia 15, 1161–1171 (2013)

    PubMed  PubMed Central  Google Scholar 

  85. A.A. Adjei, D.A. Richards, A. El-Khoueiry, F. Braiteh, C.H. Becerra, J.J. Stephenson Jr., A.F. Hezel, M. Sherman, L. Garbo, D.P. Leffingwell, C. Iverson, J.N. Miner, Z. Shen, L.T. Yeh, S. Gunawan, D.M. Wilson, K.J. Manhard, P. Rajagopalan, H. Krissel, N.J. Clendeninn, A phase I study of the safety, pharmacokinetics, and pharmacodynamics of combination therapy with Refametinib plus Sorafenib in patients with advanced cancer. Clin. Cancer Res. 22, 2368–2376 (2016)

    CAS  PubMed  Google Scholar 

  86. J.R. Infante, L.A. Fecher, G.S. Falchook, S. Nallapareddy, M.S. Gordon, C. Becerra, D.J. DeMarini, D.S. Cox, Y. Xu, S.R. Morris, V.G. Peddareddigari, N.T. Le, L. Hart, J.C. Bendell, G. Eckhardt, R. Kurzrock, K. Flaherty, H.A. Burris 3rd., W.A. Messersmith, Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 13, 773–781 (2012)

    CAS  PubMed  Google Scholar 

  87. G. Kan, Z. Wang, C. Sheng, G. Chen, C. Yao, Y. Mao, S. Chen, Dual inhibition of DKC1 and MEK1/2 synergistically restrains the growth of colorectal cancer cells. Adv. Sci. (Weinh) 8, 2004344 (2021)

    CAS  PubMed  Google Scholar 

  88. S.A. Blankenstein, M.W. Rohaan, W.M.C. Klop, B. van der Hiel, B.A. van de Wiel, M.J. Lahaye, S. Adriaansz, K. Sikorska, H. van Tinteren, A. Sari, L.G. Grijpink-Ongering, W.J. van Houdt, M. Wouters, C.U. Blank, S. Wilgenhof, J.V. van Thienen, A.C.J. van Akkooi, J. Haanen, Neoadjuvant Cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection, REDUCTOR: A prospective, single-arm, open-label phase II trial. Ann. Surg. 274, 383–389 (2021)

    PubMed  Google Scholar 

  89. X. Zhou, A. Zhu, X. Gu, G. Xie, Inhibition of MEK suppresses hepatocellular carcinoma growth through independent MYC and BIM regulation. Cell Oncol. (Dordr) 42, 369–380 (2019)

    CAS  PubMed  Google Scholar 

  90. L. Paragh, D. Törőcsik, Factor XIII Subunit A in the skin: applications in diagnosis and treatment. Biomed. Res. Int. 2017, 3571861 (2017)

    PubMed  PubMed Central  Google Scholar 

  91. M.T. Kaartinen, M. Arora, S. Heinonen, A. Rissanen, J. Kaprio, K.H. Pietiläinen, Transglutaminases and obesity in humans: Association of F13A1 to adipocyte hypertrophy and adipose tissue immune response. Int. J. Mol. Sci. 21, 8289 (2020)

  92. Y. Wang, K. Yan, J. Lin, J. Li, J. Bi, Macrophage M2 co-expression factors correlate with the immune microenvironment and predict outcome of renal clear cell carcinoma. Front. Genet. 12, 615655 (2021)

    CAS  PubMed  PubMed Central  Google Scholar 

  93. R. Adány, Z. Nemes, L. Muszbek, Characterization of factor XIII containing-macrophages in lymph nodes with Hodgkin’s disease. Br. J. Cancer 55, 421–426 (1987)

    PubMed  PubMed Central  Google Scholar 

  94. L. Maiuri, A. Luciani, I. Giardino, V. Raia, V.R. Villella, M. D’Apolito, M. Pettoello-Mantovani, S. Guido, C. Ciacci, M. Cimmino, O.N. Cexus, M. Londei, S. Quaratino, Tissue transglutaminase activation modulates inflammation in cystic fibrosis via PPARgamma down-regulation. J. Immunol. 180, 7697–7705 (2008)

    CAS  PubMed  Google Scholar 

  95. C. Klöck, T.R. Diraimondo, C. Khosla, Role of transglutaminase 2 in celiac disease pathogenesis. Semin. Immunopathol. 34, 513–522 (2012)

    PubMed  PubMed Central  Google Scholar 

  96. T. Su, X.Y. Qin, Y. Furutani, Transglutaminase 2 as a marker for inflammation and therapeutic target in sepsis. Int J Mol Sci 22, 1897 (2021)

  97. L. Cao, M. Shao, J. Schilder, T. Guise, K.S. Mohammad, D. Matei, Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. Oncogene 31, 2521–2534 (2012)

    CAS  PubMed  Google Scholar 

  98. J. Fu, Q.Y. Yang, K. Sai, F.R. Chen, J.C. Pang, H.K. Ng, A.L. Kwan, Z.P. Chen, TGM2 inhibition attenuates ID1 expression in CD44-high glioma-initiating cells. Neuro Oncol. 15, 1353–1365 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  99. K. Oh, H.G. Moon, D.S. Lee, Y.B. Yoo, Tissue transglutaminase-interleukin-6 axis facilitates peritoneal tumor spreading and metastasis of human ovarian cancer cells. Lab. Anim. Res. 31, 188–197 (2015)

    PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82173153, 81902370, 81972582 and 92168111) and the Natural Science Foundation of Shanghai (19ZR1452500).

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Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China

    Shan Zhang, Hui Li, Shu-Heng Jiang, Zhi-Gang Zhang & Xiao-Mei Yang

  2. Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200217, People’s Republic of China

    Hong-Fei Yao

  3. Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China

    Tong Su

  4. Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, 1800 Yuntai Road, Pudong District, Shanghai, 200123, China

    Hao Wang

  5. Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, People’s Republic of China

    Fang-Yuan Dong

  6. Shanghai Institute of Precision Medicine, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Qin Yang

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  1. Shan Zhang
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Contributions

Conception and design: Q. Yang, XM Yang, FY Dong, ZG Zhang; Development of methodology: S. Zhang, Q. Yang; Acquisition of data: S. Zhang, H. Li, Q. Yang, HF Yao, T. Su, W. Hao, SH Jiang; Analysis and interpretation of data: S. Zhang, Q. Yang, XM Yang, T. Su, H. Li, FY Dong, SH Jiang; Writing, review and/or revision of the manuscript: S. Zhang, Q. Yang, XM Yang, FY. Dong, ZG Zhang; Administrative, technical or material support: Q. Yang, FY Dong, ZG Zhang, XM Yang. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Zhi-Gang Zhang, Fang-Yuan Dong, Qin Yang or Xiao-Mei Yang.

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Ethical approval

Studies using human PDAC samples were approved by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University (No. RA-2019–116). The animal experiments according to the protocols were approved by the Shanghai Jiao Tong University Animal Care Commission and all mice received humane care in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

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Shan Zhang, Hong-Fei Yao, Hui Li and Tong Su share co-first authorship.

Supplementary Information

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Supplementary Figure 1

The prognostic value of the TG score in KIRC, LUSC, PAAD, and STAD. Time-dependent receiver operating characteristic (ROC) curves of the prognostic TG score model in TGCA-KIRC (A–C), TGCA-LUSC (D–F), TGCA-PAAD (G–I), and TGCA-STAD (J–L). The X-axis shows the false-positive rates, and the Y-axis shows the true-positive rates (PNG 233 kb)

High resolution image (TIF 5.34 MB)

Supplementary Figure 2

Mutation and CNV of TG family genes across cancers. (A) Point mutation frequency in TG family genes across TCGA cancer types. (B) The frequencies of missense variants and loss-of-function mutations in TG family genes in 20 TCGA cancer types. The highest frequency of mutations in TG family genes was observed in UCEC. (C) The frequency of copy number variations in TG family genes in different TCGA cancers. The gradient of colors in the bubble map represents the log2-fold change between cancer and normal tissues. The purple nodes indicate high expression in cancer, while the green nodes indicate low expression in cancer. The red circles represent copy number amplification, whereas the blue circles represent deletion (PNG 197 kb)

High resolution image (TIF 3.76 MB)

Supplementary Figure 3

The relationships between TG expression and drug sensitivity based on the Cancer Cell Line Encyclopedia (CCLE) database. The gradient of colors in the bubble map represents the R-value. Purple indicates a positive correlation with sensitivity to the drug candidates, while green indicates a negative correlation. The size of the nodes represents the statistical significance; the larger the size is, the greater the significance (PNG 119 kb)

High resolution image (TIF 1.69 MB)

Supplementary Figure 4

The relationship between TG expression and drug sensitivity based on the Genomics of Drug Sensitivity in Cancer (GDSC) database. The gradient of colors in the bubble map represents the R-value. Purple indicates a positive correlation with sensitivity to the drug candidates, while green indicates a negative correlation. The size of the nodes represents the statistical significance; the larger the size is, the greater the significance (PNG 585 kb)

High resolution image (TIF 8.28 MB)

Supplementary Figure 5

(A) Western blotting analysis of the knockdown efficiency of TGM2 in panc1 and patu-8988 cells. (B) Western blotting analysis of the knockdown and overexpression efficiency of Tgm2 in KPC1199 cells. (C) Analysis of CCL2 expression in TGM2 overexpression and control pancreatic cancer cells (n=3 replicates per group, means ± standard deviations, one of three biological replicates). *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 (PNG 922 kb)

High resolution image (TIF 2.41 MB)

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Zhang, S., Yao, HF., Li, H. et al. Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer. Cell Oncol. 46, 1473–1492 (2023). https://doi.org/10.1007/s13402-023-00824-7

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