- Open Access
Tissue transglutaminase-interleukin-6 axis facilitates peritoneal tumor spreading and metastasis of human ovarian cancer cells
Laboratory Animal Research volume 31, pages188–197(2015)
Inflammation has recently been implicated in cancer formation and progression. As tissue transglutaminase (TG2) has been associated with both inflammatory signaling and tumor cell behavior, we propose that TG2 may be an important link inducing interleukin-6 (IL-6)-mediated cancer cell aggressiveness, including cancer stem cell-like characteristics and distant hematogenous metastasis. We evaluated the effect of differential TG2 and IL-6 expression on in vivo distant metastasis of human ovarian cancer cells. IL-6 production in human ovarian cancer cells was dependent on their TG2 expression levels. The size and efficiency of tumor sphere formation were correlated with TG2 expression levels and were dependent on TG2-mediated IL-6 secretion in human ovarian cancer cells. Primary tumor growth and propagation in the peritoneum and distant hematogenous metastasis into the liver and lung were also dependent on TG2 and downstream IL-6 expression levels in human ovarian cancer cells. In this report, we provide evidence that TG2 is an important link in IL-6-mediated tumor cell aggressiveness, and that TG2 and downstream IL-6 could be important mediators of distant hematogenous metastasis of human ovarian cancer cells. Intervention specific to TG2 and/or downstream IL-6 in ovarian cancer cells could provide a promising means to control tumor metastasis.
Lorand, L, Graham, RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 2003; 4(2): 140–156.
Fesus, L, Piacentini, M. Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci 2002; 27(10): 534–539.
Mehta, K. Biological and therapeutic significance of tissue transglutaminase in pancreatic cancer. Amino Acids 2009; 36(4): 709–716.
Mehta, K, Fok, J, Miller, FR, Koul, D, Sahin, AA. Prognostic significance of tissue transglutaminase in drug resistant and metastatic breast cancer. Clin Cancer Res 2004; 10(23): 8068–8076.
Verma, A, Mehta, K. Tissue transglutaminase-mediated chemoresistance in cancer cells. Drug Resist Updat 2007; 10(4-5): 144–151.
Verma, A, Wang, H, Manavathi, B, Fok, JY, Mann, AP, Kumar, R, Mehta, K. Increased expression of tissue transglutaminase in pancreatic ductal adenocarcinoma and its implications in drug resistance and metastasis. Cancer Res 2006; 66(1): 10525–10533.
Antonyak, MA, Miller, AM, Jansen, JM, Boehm, JE, Balkman, CE, Wakshlag, JJ, Page, RL, Cerione, RA. Augmentation of tissue transglutaminase expression and activation by epidermal growth factor inhibit doxorubicin-induced apoptosis in human breast cancer cells. J Biol Chem 2004; 279(40): 41461–41467.
Ai, L, Kim, WJ, Demircan, B, Dyer, LM, Bray, KJ, Skehan, RR, Massoll, NA, Brown, KD. The transglutaminase 2 gene (TGM2), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis 2008; 29(3): 510–518.
Chi, DS, Sabbatini, P. Advanced ovarian cancer. Curr Treat Options Oncol 2000; 1(2): 139–146.
Hwang, JY, Mangala, LS, Fok, JY, Lin, YG, Merritt, WM, Spannuth WA, Nick, AM, Fiterman, DJ, Vivas-Mejia, PE, Deavers, MT, Coleman, RL, Lopez-Berestein, G, Mehta, K, Sood, AK. Clinical and biological significance of tissue transglutaminase in ovarian carcinoma. Cancer Res 2008; 68(14): 5849–5858.
Satpathy, M, Cao, L, Pincheira, R, Emerson, R, Bigsby, R, Nakshatri H, Matei, D. Enhanced peritoneal ovarian tumor dissemination by tissue transglutaminase. Cancer Res 2007; 67(15): 7194–7202.
Cao, L, Petrusca, DN, Satpathy, M, Nakshatri, H, Petrache, I, Matei D. Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting cell survival signaling. Carcinogenesis 2008; 29(10): 1893–1900.
Mangala, LS, Fok, JY, Zorrilla-Calancha, IR, Verma, A, Mehta, K. Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells. Oncogene 2007; 26(17): 2459–2470.
Verma, A, Guha, S, Wang, H, Fok, JY, Koul, D, Abbruzzese, J, Mehta K. Tissue transglutaminase regulates focal adhesion kinase/AKT activation by modulating PTEN expression in pancreatic cancer cells. Clin Cancer Res 2008; 14(7): 1997–2005.
Antonyak, MA, Li, B, Regan, AD, Feng, Q, Dusaban, SS, Cerione RA. Tissue transglutaminase is an essential participant in the epidermal growth factor-stimulated signaling pathway leading to cancer cell migration and invasion. J Biol Chem 2009; 284(27): 17914–17925.
Kim, DS, Park, SS, Nam, BH, Kim, IH, Kim, SY. Reversal of drug resistance in breast cancer cells by transglutaminase 2 inhibition and nuclear factor-kappaB inactivation. Cancer Res 2006; 66(22): 10936–10943.
Mann, AP, Verma, A, Sethi, G, Manavathi, B, Wang, H, Fok, JY, Kunnumakkara, AB, Kumar, R, Aggarwal, BB, Mehta, K. Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-kappaB in cancer cells: delineation of a novel pathway. Cancer Res 2006; 66(17): 8788–8795.
Jang, GY, Jeon, JH, Cho, SY, Shin, DM, Kim, CW, Jeong, EM, Bae HC, Kim, TW, Lee, SH, Choi, Y, Lee, DS, Park, SC, Kim, IG. Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB activity in hypoxic tumor cells. Oncogene 2010; 29(3): 356–367.
Lee, J, Kim, YS, Choi, DH, Bang, MS, Han, TR, Joh, TH, Kim, SY. Transglutaminase 2 induces nuclear factor-kappaB activation via a novel pathway in BV-2 microglia. J Biol Chem 2004; 279(51): 53725–53735.
Knüpfer, H, Preiss, R. Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat 2007; 102(2): 129–135.
Bachelot, T, Ray-Coquard, I, Menetrier-Caux, C, Rastkha, M, Duc A, Blay, JY. Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. Br J Cancer 2003; 88(11): 1721–1726.
Grivennikov, S, Karin, E, Terzic, J, Mucida, D, Yu, GY, Vallabhapurapu, S, Scheller, J, Rose-John, S, Cheroutre, H, Eckmann, L, Karin, M. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009; 15(2): 103–113.
Huber, MA, Azoitei, N, Baumann, B, Grünert, S, Sommer, A, Pehamberger, H, Kraut, N, Beug, H, Wirth, T. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004; 114(4): 569–581.
Sullivan, NJ, Sasser, AK, Axel, AE, Vesuna, F, Raman, V, Ramirez N, Oberyszyn, TM, Hall, BM. Interleukin-6 induces an epithelialmesenchymal transition phenotype in human breast cancer cells. Oncogene 2009; 28(33): 2940–2947.
Sansone, P, Storci, G, Tavolari, S, Guarnieri, T, Giovannini, C, Taffurelli, M, Ceccarelli, C, Santini, D, Paterini, P, Marcu, KB, Chieco, P, Bonafè M. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 2007; 117(17): 3988–4002.
Pardal, R, Clarke, MF, Morrison, SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003; 3(12): 895–902.
Oh, K, Park, HB, Byoun, OJ, Shin, DM, Jeong, EM, Kim, YW, Kim YS, Melino, G, Kim, IG, Lee, DS. Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice. J Exp Med 2011; 208(8): 1707–1719.
Schäfer, M, Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 2008; 9(8): 628–638.
Collighan, RJ, Griffin, M. Transglutaminase 2 cross-linking of matrix proteins: biological significance and medical applications. Amino Acids 2009; 36(4): 659–670.
Mani, SA, Guo, W, Liao, MJ, Eaton, EN, Ayyanan, A, Zhou, AY, Brooks, M, Reinhard, F, Zhang, CC, Shipitsin, M, Campbell, LL, Polyak, K, Brisken, C, Yang, J, Weinberg, RA. The epithelialmesenchymal transition generates cells with properties of stem cells. Cell 2008; 133(4): 704–715.
Sodek, KL, Ringuette, MJ, Brown, TJ. Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype. Int J Cancer 2009; 124(9): 2060–2070.
Ito, M, Hiramatsu, H, Kobayashi, K, Suzue, K, Kawahata, M, Hioki K, Ueyama, Y, Koyanagi, Y, Sugamura, K, Tsuji, K, Heike, T, Nakahata, T. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 2002; 100(9): 3175–3182.
Verderio, EA, Telci, D, Okoye, A, Melino, G, Griffin, M. A novel RGD-independent cel adhesion pathway mediated by fibronectinbound tissue transglutaminase rescues cells from anoikis. J Biol Chem 2003; 278(43): 42604–42614.
Satpathy, M, Shao, M, Emerson, R, Donner, DB, Matei, D. Tissue transglutaminase regulates matrix metalloproteinase-2 in ovarian cancer by modulating cAMP-response element-binding protein activity. J Biol Chem 2009; 284(23): 15390–15399.
Chiarugi, P, Giannoni, E. Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol 2008; 76(11): 1352–1364.
Kim, MY, Oskarsson, T, Acharyya, S, Nguyen, DX, Zhang, XH, Norton, L, Massagué J. Tumor self-seeding by circulating cancer cells. Cell 2009; 139(7): 1315–1326.
Daniel, D, Wilson, NS. Tumor necrosis factor: renaissance as a cancer therapeutic? Curr Cancer Drug Targets 2008; 8(2): 124- 131
Takahashi, E, Nagano, O, Ishimoto, T, Yae, T, Suzuki, Y, Shinoda, T, Nakamura, S, Niwa, S, Ikeda, S, Koga, H, Tanihara, H, Saya, H. Tumor necrosis factor-alpha regulates transforming growth factorbeta-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction. J Biol Chem 2010; 285(6): 4060–4073.
Chung, YJ, Park, BB, Kang, YJ, Kim, TM, Eaves, CJ, Oh, IH. Unique effects of Stat3 on the early phase of hematopoietic stem cell regeneration. Blood 2006; 108(4): 1208–1215.
Müller, S, Chakrapani, BP, Schwegler, H, Hofmann, HD, Kirsch, M. Neurogenesis in the dentate gyrus depends on ciliary neurotrophic factor and signal transducer and activator of transcription 3 signaling. Stem Cells 2009; 27(2): 431–441.
Thiery, JP, Acloque, H, Huang, RY, Nieto, MA. Epithelialmesenchymal transitions in development and disease. Cell 2009; 139(5): 871–890.
Shao, M, Cao, L, Shen, C, Satpathy, M, Chelladurai, B, Bigsby, RM, Nakshatri, H, Matei, D. Epithelial-to-mesenchymal transition and ovarian tumor progression induced by tissue transglutaminase. Cancer Res 2009; 69(24): 9192–9201.
Kumar, A, Xu, J, Brady, S, Gao, H, Yu, D, Reuben, J, Mehta, K. Tissue transglutaminase promotes drug resistance and invasion by inducing mesenchymal transition in mammary epithelial cells. PLoS One 2010; 5(10): e13390.
Yuan, L, Siegel, M, Choi, K, Khosla, C, Miller, CR, Jackson, EN, Piwnica-Worms, D, Rich, KM. Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy. Oncogene 2007; 26(18): 2563–2573.
Kojima, S, Nara, K, Rifkin, DB. Requirement for transglutaminase in the activation of latent transforming growth factor-beta in bovine endothelial cells. J Cell Biol 1993; 121(2): 439–448.
Singer, CF, Hudelist, G, Walter, I, Rueckliniger, E, Czerwenka, K, Kubista, E, Huber, AV. Tissue array-based expression of transglutaminase-2 in human breast and ovarian cancer. Clin Exp Metastasis 2006; 23(1): 33–39.
About this article
Cite this article
Oh, K., Moon, H., Lee, D. et al. Tissue transglutaminase-interleukin-6 axis facilitates peritoneal tumor spreading and metastasis of human ovarian cancer cells. Lab Anim Res 31, 188–197 (2015). https://doi.org/10.5625/lar.2015.31.4.188
- Tissue transglutaminase
- human ovarian cancer