HMGB1: an overview of its versatile roles in the pathogenesis of colorectal cancer

  • Kim Jun Cheng
  • Mohammed Abdullah Alshawsh
  • Elsa Haniffah Mejia Mohamed
  • Surendran Thavagnanam
  • Ajantha Sinniah
  • Zaridatul Aini IbrahimEmail author



In recent years, the high mobility group box-1 (HMGB1) protein, a damage-associated molecular pattern (DAMP) molecule, has been found to play multifunctional roles in the pathogenesis of colorectal cancer. Although much attention has been given to the diagnostic and prognostic values of HMGB1 in colorectal cancer, the exact functional roles of the protein as well as the mechanistic pathways involved have remained poorly defined. This systematic review aims to discuss what is currently known about the roles of HMGB1 in colorectal cancer development, growth and progression, and to highlight critical areas for future investigations. To achieve this, the bibliographic databases Pubmed, Scopus, Web of Science and ScienceDirect were systematically screened for articles from inception till June 2018, which address associations of HMGB1 with colorectal cancer.


HMGB1 plays multiple roles in promoting the pathogenesis of colorectal cancer, despite a few contradicting studies. HMGB1 may differentially regulate disease-related processes, depending on the redox status of the protein in colorectal cancer. Binding of HMGB1 to various protein partners may alter the impact of HMGB1 on disease progression. As HMGB1 is heavily implicated in the pathogenesis of colorectal cancer, it is crucial to further improve our understanding of the functional roles of HMGB1 not only in colorectal cancer, but ultimately in all types of cancers.


Colorectal cancer High mobility group box 1 DAMP 



All authors would like to thank Thanusha Ganesan for her kind assistance and contributions.

Funding information

This research was supported by the University of Malaya Research Fund Assistance (BKP) (Grant no. BK021–2018).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

13402_2019_477_MOESM1_ESM.docx (68 kb)
ESM 1 (DOCX 67 kb)
13402_2019_477_MOESM2_ESM.pptx (64 kb)
ESM 2 Supplementary Fig. 1. Overall Kaplan-Meier survival estimates (adapted from [104, 105]). Cases without genetic alterations in HMGB1, shown in blue (n = 509), exhibit lower overall survival rates compared to cases without, shown in red (n = 13). (PPTX 63 kb)
13402_2019_477_MOESM3_ESM.pptx (63 kb)
ESM 3 Supplementary Fig. 2. Disease/progression-free Kaplan-Meier estimates (adapted from [104, 105]). Cases without genetic alterations in HMGB1, shown in blue (n = 188), exhibit higher relapse rates compared to cases without, shown in red (n = 9). (PPTX 63 kb)


  1. 1.
    T. Ueda, M. Yoshida, HMGB proteins and transcriptional regulation. Biochim Biophys Acta 1799, 114–118 (2010)CrossRefPubMedGoogle Scholar
  2. 2.
    T. Gemoll, J.K. Habermann, S. Becker, S. Szymczak, M.B. Upender, H.P. Bruch, U. Hellman, T. Ried, G. Auer, H. Jornvall, U.J. Roblick, Chromosomal aneuploidy affects the global proteome equilibrium of colorectal cancer cells. Anal Cell Pathol 36, 149–161 (2013)CrossRefGoogle Scholar
  3. 3.
    R. Kang, Q. Zhang, H.J. Zeh 3rd, M.T. Lotze, D. Tang, HMGB1 in cancer: Good, bad, or both? Clin Cancer Res 19, 4046–4057 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    H.X. Yan, H.P. Wu, H.L. Zhang, C. Ashton, C. Tong, H. Wu, Q.J. Qian, H.Y. Wang, Q.L. Ying, p53 promotes inflammation-associated hepatocarcinogenesis by inducing HMGB1 release. J Hepatol 59, 762–768 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    P. Scaffidi, T. Misteli, M.E. Bianchi, Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 418, 191–195 (2002)CrossRefPubMedGoogle Scholar
  6. 6.
    C. Janko, M. Filipović, L.E. Munoz, C. Schorn, G. Schett, I. Ivanović-Burmazović, M. Herrmann, Redox modulation of HMGB1-related signaling. Antioxid Redox Signal 20, 1075–1085 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    E. Venereau, M. Casalgrandi, M. Schiraldi, D.J. Antoine, A. Cattaneo, F. De Marchis, J. Liu, A. Antonelli, A. Preti, L. Raeli, S.S. Shams, H. Yang, L. Varani, U. Andersson, K.J. Tracey, A. Bachi, M. Uguccioni, M.E. Bianchi, Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med 209, 1519–1528 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    D.J. Antoine, H.E. Harris, U. Andersson, K.J. Tracey, M.E. Bianchi, A systematic nomenclature for the redox states of high mobility group box (HMGB) proteins. Mol Med 20, 135–137 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    J. Terzić, S. Grivennikov, E. Karin, M. Karin, Inflammation and Colon Cancer. Gastroenterology 138, 2101–2114.e2105 (2010)CrossRefPubMedGoogle Scholar
  10. 10.
    F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394–424 (2018)CrossRefPubMedGoogle Scholar
  11. 11.
    M.E. Bianchi, DAMPs, PAMPs and alarmins: All we need to know about danger. J Leukoc Biol 81, 1–5 (2007)CrossRefPubMedGoogle Scholar
  12. 12.
    U. Andersson, K.J. Tracey, HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol 29, 139–162 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    D. Tang, R. Kang, H.J. Zeh III, M.T. Lotze, High-mobility group box 1 and cancer. Biochim Biophys Acta 1799, 131–140 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    H. Wang, O. Bloom, M. Zhang, J.M. Vishnubhakat, M. Ombrellino, J. Che, A. Frazier, H. Yang, S. Ivanova, L. Borovikova, K.R. Manogue, E. Faist, E. Abraham, J. Andersson, U. Andersson, P.E. Molina, N.N. Abumrad, A. Sama, K.J. Tracey, HMG-1 as a late mediator of endotoxin lethality in mice. Science. 285, 248–251 (1999)CrossRefPubMedGoogle Scholar
  15. 15.
    H. Yang, H. Wang, S.S. Chavan, U. Andersson, High mobility group box protein 1 (HMGB1): The prototypical endogenous danger molecule. Mol Med 21(Suppl 1), S6–S12 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Z. Li, H. Wang, B. Song, Y. Sun, J. Han, Z. Xu, [Expression of high mobility group box-1 in colorectal cancer and its clinical significance]. Zhonghua Wei Chang Wai Ke Za Zhi. 18, 616–619 (2015)Google Scholar
  17. 17.
    D. Süren, M. Yıldırım, Ö. Demirpençe, V. Kaya, A.S. Alikanoğlu, N. Bülbüller, M. Yıldız, C. Sezer, The role of high mobility group box 1 (HMGB1) in colorectal cancer. Med Sci Monit 20, 530–537 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    M. Ueda, Y. Takahashi, Y. Shinden, S. Sakimura, H. Hirata, R. Uchi, Y. Takano, J. Kurashige, T. Iguchi, H. Eguchi, K. Sugimachi, H. Yamamoto, Y. Doki, M. Mori, K. Mimori, Prognostic significance of high mobility group box 1 (HMGB1) expression in patients with colorectal cancer. Anticancer Res 34, 5357–5362 (2014)PubMedPubMedCentralGoogle Scholar
  19. 19.
    X. Zhang, J. Yu, M. Li, H. Zhu, X. Sun, L. Kong, The association of HMGB1 expression with clinicopathological significance and prognosis in Asian patients with colorectal carcinoma: A meta-analysis and literature review. Onco Targets Ther 9, 4901–4911 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    H.J. Kang, H. Lee, H.-J. Choi, J.H. Youn, J.-S. Shin, Y.H. Ahn, J.S. Yoo, Y.-K. Paik, H. Kim, Non-histone nuclear factor HMGB1 is phosphorylated and secreted in colon cancers. Lab Investig 89, 948 (2009)CrossRefPubMedGoogle Scholar
  21. 21.
    Y.R. Choi, H. Kim, H.J. Kang, N.G. Kim, J.J. Kim, K.S. Park, Y.K. Paik, H.O. Kim, H. Kim, Overexpression of high mobility group box 1 in gastrointestinal stromal tumors with KIT mutation. Cancer Res 63, 2188–2193 (2003)PubMedGoogle Scholar
  22. 22.
    K. Völp, M.L. Brezniceanu, S. Bösser, T. Brabletz, T. Kirchner, D. Göttel, S. Joos, M. Zörnig, Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas. Gut. 55, 234–242 (2006)CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    L. Cottone, A. Capobianco, C. Gualteroni, C. Perrotta, M.E. Bianchi, P. Rovere-Querini, A.A. Manfredi, 5-fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells. Int J Cancer 136, 1381–1389 (2015)CrossRefPubMedGoogle Scholar
  24. 24.
    S. Maeda, Y. Hikiba, W. Shibata, T. Ohmae, A. Yanai, K. Ogura, S. Yamada, M. Omata, Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer. Biochem Biophys Res Commun 360, 394–400 (2007)CrossRefPubMedGoogle Scholar
  25. 25.
    T. Aychek, K. Miller, O. Sagi-Assif, O. Levy-Nissenbaum, M. Israeli-Amit, M. Pasmanik-Chor, J. Jacob-Hirsch, N. Amariglio, G. Rechavi, I.P. Witz, E-selectin regulates gene expression in metastatic colorectal carcinoma cells and enhances HMGB1 release. Int J Cancer 123, 1741–1750 (2008)CrossRefPubMedGoogle Scholar
  26. 26.
    H. Kuniyasu, Y. Chihara, H. Kondo, Differential effects between amphoterin and advanced glycation end products on colon cancer cells. Int J Cancer 104, 722–727 (2003)CrossRefPubMedGoogle Scholar
  27. 27.
    K.S. Chandrasekaran, A. Sathyanarayanan, D. Karunagaran, Downregulation of HMGB1 by miR-34a is sufficient to suppress proliferation, migration and invasion of human cervical and colorectal cancer cells. Tumour Biol 37, 13155–13166 (2016)CrossRefPubMedGoogle Scholar
  28. 28.
    L. Zhu, X. Li, Y. Chen, J. Fang, Z. Ge, High-mobility group box 1: A novel inducer of the epithelial-mesenchymal transition in colorectal carcinoma. Cancer Lett 357, 527–534 (2015)CrossRefPubMedGoogle Scholar
  29. 29.
    Z. Zhang, M. Wang, L. Zhou, X. Feng, J. Cheng, Y. Yu, Y. Gong, Y. Zhu, C. Li, L. Tian, Q. Huang, Increased HMGB1 and cleaved caspase-3 stimulate the proliferation of tumor cells and are correlated with the poor prognosis in colorectal cancer. J Exp Clin Cancer Res 34, 51 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    L. Cottone, A. Capobianco, C. Gualteroni, A. Monno, I. Raccagni, S. Valtorta, T. Canu, T. Di Tomaso, A. Lombardo, A. Esposito, R.M. Moresco, A.D. Maschio, L. Naldini, P. Rovere-Querini, M.E. Bianchi, A.A. Manfredi, Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis. Oncoimmunology. 5, e1122860 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    X. Chen, X. Liu, B. He, Y. Pan, H. Sun, T. Xu, X. Hu, S. Wang, MiR-216b functions as a tumor suppressor by targeting HMGB1-mediated JAK2/STAT3 signaling way in colorectal cancer. Am J Cancer Res 7, 2051–2069 (2017)PubMedPubMedCentralGoogle Scholar
  32. 32.
    S. Sharma, A. Evans, E. Hemers, Mesenchymal-epithelial signalling in tumour microenvironment: Role of high-mobility group box 1. Cell Tissue Res 365, 357–366 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    L. Zhu, L. Ren, Y. Chen, J. Fang, Z. Ge, X. Li, Redox status of high-mobility group box 1 performs a dual role in angiogenesis of colorectal carcinoma. J Cell Mol Med 19, 2128–2135 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Y. Li, J. He, D. Zhong, J. Li, H. Liang, High-mobility group box 1 protein activating nuclear factor-kappaB to upregulate vascular endothelial growth factor C is involved in lymphangiogenesis and lymphatic node metastasis in colon cancer. J Int Med Res 43, 494–505 (2015)CrossRefPubMedGoogle Scholar
  35. 35.
    J.R. van Beijnum, R.P. Dings, E. van der Linden, B.M. Zwaans, F.C. Ramaekers, K.H. Mayo, A.W. Griffioen, Gene expression of tumor angiogenesis dissected: Specific targeting of colon cancer angiogenic vasculature. Blood. 108, 2339–2348 (2006)CrossRefPubMedGoogle Scholar
  36. 36.
    H. Kikuchi, H. Yagi, H. Hasegawa, Y. Ishii, K. Okabayashi, M. Tsuruta, G. Hoshino, A. Takayanagi, Y. Kitagawa, Therapeutic potential of transgenic mesenchymal stem cells engineered to mediate anti-high mobility group box 1 activity: Targeting of colon cancer. J Surg Res 190, 134–143 (2014)CrossRefPubMedGoogle Scholar
  37. 37.
    J.R. van Beijnum, P. Nowak-Sliwinska, E. van den Boezem, P. Hautvast, W.A. Buurman, A.W. Griffioen, Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. Oncogene. 32, 363–374 (2013)CrossRefPubMedGoogle Scholar
  38. 38.
    Y. Zheng, G. Zhu, HMGB1 suppresses colon carcinoma cell apoptosis triggered by coculture with dendritic cells via an ER stressassociated autophagy pathway. Mol Med Rep 17, 3123–3132 (2018)PubMedPubMedCentralGoogle Scholar
  39. 39.
    W. Liu, Z. Zhang, Y. Zhang, X. Chen, S. Guo, Y. Lei, Y. Xu, C. Ji, Z. Bi, K. Wang, HMGB1-mediated autophagy modulates sensitivity of colorectal cancer cells to oxaliplatin via MEK/ERK signaling pathway. Cancer Biol Ther 16, 511–517 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Y. Luo, J. Yoneda, H. Ohmori, T. Sasaki, K. Shimbo, S. Eto, Y. Kato, H. Miyano, T. Kobayashi, T. Sasahira, Y. Chihara, H. Kuniyasu, Cancer usurps skeletal muscle as an energy repository. Cancer Res 74, 330–340 (2014)CrossRefPubMedGoogle Scholar
  41. 41.
    Z. Wang, X. Wang, J. Li, C. Yang, Z. Xing, R. Chen, F. Xu, HMGB1 knockdown effectively inhibits the progression of rectal cancer by suppressing HMGB1 expression and promoting apoptosis of rectal cancer cells. Mol Med Rep 14, 1026–1032 (2016)CrossRefPubMedGoogle Scholar
  42. 42.
    G. Gdynia, S.W. Sauer, J. Kopitz, D. Fuchs, K. Duglova, T. Ruppert, M. Miller, J. Pahl, A. Cerwenka, M. Enders, H. Mairbaurl, M.M. Kaminski, R. Penzel, C. Zhang, J.C. Fuller, R.C. Wade, A. Benner, J. Chang-Claude, H. Brenner, M. Hoffmeister, H. Zentgraf, P. Schirmacher, W. Roth, The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration. Nat Commun 7, 10764 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    C.C. Zhang, G. Gdynia, V. Ehemann, W. Roth, The HMGB1 protein sensitizes colon carcinoma cells to cell death triggered by pro-apoptotic agents. Int J Oncol 46, 667–676 (2015)CrossRefPubMedGoogle Scholar
  44. 44.
    K.R. Reed, F. Song, M.A. Young, N. Hassan, D.J. Antoine, N.-P.B. Gemici, A.R. Clarke, J.R. Jenkins, Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype. Oncotarget. 7, 51665–51673 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Y. Luo, Y. Chihara, K. Fujimoto, T. Sasahira, M. Kuwada, R. Fujiwara, K. Fujii, H. Ohmori, H. Kuniyasu, High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy. Eur J Cancer 49, 741–751 (2013)CrossRefPubMedGoogle Scholar
  46. 46.
    Y. Luo, H. Ohmori, K. Fujii, Y. Moriwaka, T. Sasahira, M. Kurihara, N. Tatsumoto, T. Sasaki, Y. Yamashita, H. Kuniyasu, HMGB1 attenuates anti-metastatic defence of the liver in colorectal cancer. Eur J Cancer 46, 791–799 (2010)CrossRefPubMedGoogle Scholar
  47. 47.
    A. Kusume, T. Sasahira, Y. Luo, M. Isobe, N. Nakagawa, N. Tatsumoto, K. Fujii, H. Ohmori, H. Kuniyasu, Suppression of dendritic cells by HMGB1 is associated with lymph node metastasis of human colon cancer. Pathobiology. 76, 155–162 (2009)CrossRefPubMedGoogle Scholar
  48. 48.
    W. Li, K. Wu, E. Zhao, L. Shi, R. Li, P. Zhang, Y. Yin, X. Shuai, G. Wang, K. Tao, HMGB1 recruits myeloid derived suppressor cells to promote peritoneal dissemination of colon cancer after resection. Biochem Biophys Res Commun 436, 156–161 (2013)CrossRefPubMedGoogle Scholar
  49. 49.
    Z. Liu, L.D. Falo Jr., Z. You, Knockdown of HMGB1 in tumor cells attenuates their ability to induce regulatory T cells and uncovers naturally acquired CD8 T cell-dependent antitumor immunity. J Immunol 187, 118–125 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    L. Apetoh, F. Ghiringhelli, A. Tesniere, M. Obeid, C. Ortiz, A. Criollo, G. Mignot, M.C. Maiuri, E. Ullrich, P. Saulnier, H. Yang, S. Amigorena, B. Ryffel, F.J. Barrat, P. Saftig, F. Levi, R. Lidereau, C. Nogues, J.P. Mira, A. Chompret, V. Joulin, F. Clavel-Chapelon, J. Bourhis, F. Andre, S. Delaloge, T. Tursz, G. Kroemer, L. Zitvogel, Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13, 1050–1059 (2007)CrossRefPubMedGoogle Scholar
  51. 51.
    R. Lotfi, G.I. Herzog, R.A. DeMarco, D. Beer-Stolz, J.J. Lee, A. Rubartelli, H. Schrezenmeier, M.T. Lotze, Eosinophils oxidize damage-associated molecular pattern molecules derived from stressed cells. J Immunol 183, 5023–5031 (2009)CrossRefPubMedGoogle Scholar
  52. 52.
    B. Frey, C. Stache, Y. Rubner, N. Werthmoller, K. Schulz, R. Sieber, S. Semrau, F. Rodel, R. Fietkau, U.S. Gaipl, Combined treatment of human colorectal tumor cell lines with chemotherapeutic agents and ionizing irradiation can in vitro induce tumor cell death forms with immunogenic potential. J Immunotoxicol 9, 301–313 (2012)CrossRefPubMedGoogle Scholar
  53. 53.
    H. Kuniyasu, T. Sasaki, T. Sasahira, H. Ohmori, T. Takahashi, Depletion of tumor-infiltrating macrophages is associated with amphoterin expression in colon cancer. Pathobiology. 71, 129–136 (2004)CrossRefPubMedGoogle Scholar
  54. 54.
    H. Kuniyasu, S. Yano, T. Sasaki, T. Sasahira, S. Sone, H. Ohmori, Colon cancer cell-derived high mobility group 1/amphoterin induces growth inhibition and apoptosis in macrophages. Am J Pathol 166, 751–760 (2005)CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    H. Kumar, T. Kawai, S. Akira, Pathogen recognition by the innate immune system. Int Rev Immunol 30, 16–34 (2011)CrossRefGoogle Scholar
  56. 56.
    J. Galon, A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pagès, M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoué, P. Bruneval, P.-H. Cugnenc, Z. Trajanoski, W.-H. Fridman, F. Pagès, Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 313, 1960–1964 (2006)CrossRefPubMedGoogle Scholar
  57. 57.
    D.I. Gabrilovich, Myeloid-derived suppressor cells. Cancer Immunol Res 5, 3–8 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    E. Tartour, H. Pere, B. Maillere, M. Terme, N. Merillon, J. Taieb, F. Sandoval, F. Quintin-Colonna, K. Lacerda, A. Karadimou, C. Badoual, A. Tedgui, W.H. Fridman, S. Oudard, Angiogenesis and immunity: A bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 30, 83–95 (2011)CrossRefPubMedGoogle Scholar
  59. 59.
    F. Shojaei, X. Wu, X. Qu, M. Kowanetz, L. Yu, M. Tan, Y.G. Meng, N. Ferrara, G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A 106, 6742–6747 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    C.A. Corzo, T. Condamine, L. Lu, M.J. Cotter, J.I. Youn, P. Cheng, H.I. Cho, E. Celis, D.G. Quiceno, T. Padhya, T.V. McCaffrey, J.C. McCaffrey, D.I. Gabrilovich, HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207, 2439–2453 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    V. Kumar, P. Cheng, T. Condamine, S. Mony, L.R. Languino, J.C. McCaffrey, N. Hockstein, M. Guarino, G. Masters, E. Penman, F. Denstman, X. Xu, D.C. Altieri, H. Du, C. Yan, D.I. Gabrilovich, CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity. 44, 303–315 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    P. Nilendu, S.C. Sarode, D. Jahagirdar, I. Tandon, S. Patil, G.S. Sarode, J.K. Pal, N.K. Sharma, Mutual concessions and compromises between stromal cells and cancer cells: Driving tumor development and drug resistance. Cell Oncol 41, 353–367 (2018)CrossRefGoogle Scholar
  63. 63.
    N. Eiro, L. Gonzalez, A. Martinez-Ordonez, B. Fernandez-Garcia, L.O. Gonzalez, S. Cid, F. Dominguez, R. Perez-Fernandez, F.J. Vizoso, Cancer-associated fibroblasts affect breast cancer cell gene expression, invasion and angiogenesis. Cell Oncol 41, 369–378 (2018)CrossRefGoogle Scholar
  64. 64.
    N. Maugeri, L. Campana, M. Gavina, C. Covino, M. De Metrio, C. Panciroli, L. Maiuri, A. Maseri, A. D'Angelo, M.E. Bianchi, P. Rovere-Querini, A.A. Manfredi, Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost 12, 2074–2088 (2014)CrossRefPubMedGoogle Scholar
  65. 65.
    A.I. Valderrama-Treviño, B. Barrera-Mera, J.C. Ceballos-Villalva, E.E. Montalvo-Javé, Hepatic metastasis from colorectal Cancer. Euroasian J Hepatogastroenterol 7, 166–175 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    C. Rüegg, Leukocytes, inflammation, and angiogenesis in cancer: Fatal attractions. J Leukoc Biol 80, 682–684 (2006)CrossRefPubMedGoogle Scholar
  67. 67.
    C.Y. Huang, S.F. Chiang, T.W. Ke, T.W. Chen, Y.C. Lan, Y.S. You, A.C. Shiau, W.T. Chen, K.S.C. Chao, Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy. Cancer Immunol Immunother 67, 551–562 (2018)CrossRefPubMedGoogle Scholar
  68. 68.
    G. van Niekerk, A.M. Engelbrecht, Role of PKM2 in directing the metabolic fate of glucose in cancer: A potential therapeutic target. Cell Oncol 41, 343–351 (2018)CrossRefGoogle Scholar
  69. 69.
    X. Zhong, B. Chen, Z. Yang, The role of tumor-associated macrophages in colorectal carcinoma progression. Cell Physiol Biochem 45, 356–365 (2018)CrossRefPubMedGoogle Scholar
  70. 70.
    F. Sipos, O. Galamb, Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon. World J Gastroenterol 18, 601–608 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    J.P. Thiery, J.P. Sleeman, Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol. 7, 131 (2006)CrossRefPubMedGoogle Scholar
  72. 72.
    C.A. Duckworth, D. Clyde, D.L. Worthley, T.C. Wang, A. Varro, D.M. Pritchard, Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice. Gastroenterology 145, 197–208.e193 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    C. Gialeli, A.D. Theocharis, N.K. Karamanos, Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 278, 16–27 (2011)CrossRefPubMedGoogle Scholar
  74. 74.
    A.W. Griffioen, G. Molema, Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52, 237–268 (2000)PubMedPubMedCentralGoogle Scholar
  75. 75.
    S.A. Stacker, M.E. Baldwin, M.G. Achen, The role of tumor lymphangiogenesis in metastatic spread. FASEB J 16, 922–934 (2002)CrossRefPubMedGoogle Scholar
  76. 76.
    J.P. Sleeman, W. Thiele, Tumor metastasis and the lymphatic vasculature. Int J Cancer 125, 2747–2756 (2009)CrossRefPubMedGoogle Scholar
  77. 77.
    K. Akagi, Y. Ikeda, M. Miyazaki, T. Abe, J. Kinoshita, Y. Maehara, K. Sugimachi, Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Cancer 83, 887–891 (2000)CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    R. Mathew, V. Karantza-Wadsworth, E. White, Role of autophagy in cancer. Nat Rev Cancer 7, 961–967 (2007)CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    R.C. Taylor, S.P. Cullen, S.J. Martin, Apoptosis: Controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9, 231 (2008)CrossRefPubMedGoogle Scholar
  80. 80.
    L.N. Kwong, W.F. Dove, APC and its modifiers in colon cancer. Adv Exp Med Biol 656, 85–106 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    O.J. Sansom, K.R. Reed, A.J. Hayes, H. Ireland, H. Brinkmann, I.P. Newton, E. Batlle, P. Simon-Assmann, H. Clevers, I.S. Nathke, A.R. Clarke, D.J. Winton, Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18, 1385–1390 (2004)CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    H. Lee, N. Shin, M. Song, U.B. Kang, J. Yeom, C. Lee, Y.H. Ahn, J.S. Yoo, Y.K. Paik, H. Kim, Analysis of nuclear high mobility group box 1 (HMGB1)-binding proteins in colon cancer cells: Clustering with proteins involved in secretion and extranuclear function. J Proteome Res 9, 4661–4670 (2010)CrossRefPubMedGoogle Scholar
  83. 83.
    J. Yun, G. Jiang, Y. Wang, T. Xiao, Y. Zhao, D. Sun, H.J. Kaplan, H. Shao, The HMGB1-CXCL12 complex promotes inflammatory cell infiltration in Uveitogenic T cell-induced chronic experimental autoimmune uveitis. Front Immunol 8, 142 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    M. Fukumoto, S. Kurisu, T. Yamada, T. Takenawa, α-Actinin-4 Enhances Colorectal Cancer Cell Invasion by Suppressing Focal Adhesion Maturation. PLoS One 10, e0120616 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Y. Hayashida, K. Honda, M. Idogawa, Y. Ino, M. Ono, A. Tsuchida, T. Aoki, S. Hirohashi, T. Yamada, E-cadherin regulates the association between beta-catenin and actinin-4. Cancer Res 65, 8836–8845 (2005)CrossRefPubMedGoogle Scholar
  86. 86.
    M.R. Rocha, P. Barcellos-de-Souza, A.C.M. Sousa-Squiavinato, P.V. Fernandes, I.M. de Oliveira, M. Boroni, J.A. Morgado-Diaz, Annexin A2 overexpression associates with colorectal cancer invasiveness and TGF-ß induced epithelial mesenchymal transition via Src/ANXA2/STAT3. Sci Rep 8, 11285 (2018)CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    R. Seth, J. Keeley, G. Abu-Ali, S. Crook, D. Jackson, M. Ilyas, The putative tumour modifier gene ATP5A1 is not mutated in human colorectal cancer cell lines but expression levels correlate with TP53 mutations and chromosomal instability. J Clin Pathol 62, 598–603 (2009)CrossRefPubMedGoogle Scholar
  88. 88.
    H. Aggelou, P. Chadla, S. Nikou, S. Karteri, I. Maroulis, H.P. Kalofonos, H. Papadaki, V. Bravou, LIMK/cofilin pathway and slingshot are implicated in human colorectal cancer progression and chemoresistance. Virchows Arch 472, 727–737 (2018)CrossRefPubMedGoogle Scholar
  89. 89.
    S. Shin, K.L. Rossow, J.P. Grande, R. Janknecht, Involvement of RNA helicases p68 and p72 in colon cancer. Cancer Res 67, 7572–7578 (2007)CrossRefPubMedGoogle Scholar
  90. 90.
    Y. Sun, M. Luo, G. Chang, W. Ren, K. Wu, X. Li, J. Shen, X. Zhao, Y. Hu, Phosphorylation of Ser6 in hnRNPA1 by S6K2 regulates glucose metabolism and cell growth in colorectal cancer. Oncol Lett 14, 7323–7331 (2017)PubMedPubMedCentralGoogle Scholar
  91. 91.
    X. Luo, J. Yao, P. Nie, Z. Yang, H. Feng, P. Chen, X. Shi, Z. Zou, FOXM1 promotes invasion and migration of colorectal cancer cells partially dependent on HSPA5 transactivation. Oncotarget. 7, 26480–26495 (2016)PubMedPubMedCentralGoogle Scholar
  92. 92.
    Q. Liao, R. Li, R. Zhou, Z. Pan, L. Xu, Y. Ding, L. Zhao, LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression. Br J Cancer 117, 563–571 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    X. Wang, H. Yu, W. Sun, J. Kong, L. Zhang, J. Tang, J. Wang, E. Xu, M. Lai, H. Zhang, The long non-coding RNA CYTOR drives colorectal cancer progression by interacting with NCL and Sam68. Mol Cancer 17, 110 (2018)CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    H.X. Li, X.Y. Sun, S.M. Yang, Q. Wang, Z.Y. Wang, Peroxiredoxin 1 promoted tumor metastasis and angiogenesis in colorectal cancer. Pathol Res Pract 214, 655–660 (2018)CrossRefPubMedGoogle Scholar
  95. 95.
    C. Li, X. Liu, Y. Liu, X. Liu, R. Wang, J. Liao, S. Wu, J. Fan, Z. Peng, B. Li, Z. Wang, Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway. Cell Death Dis 9, 1009 (2018)CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    B. Zhang, S. Dong, R. Zhu, C. Hu, J. Hou, Y. Li, Q. Zhao, X. Shao, Q. Bu, H. Li, Y. Wu, X. Cen, Y. Zhao, Targeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4E and FGFR3. Oncotarget. 6, 22799–22811 (2015)PubMedPubMedCentralGoogle Scholar
  97. 97.
    J. Chen, Y. Wei, Q. Feng, L. Ren, G. He, W. Chang, D. Zhu, T. Yi, Q. Lin, W. Tang, J. Xu, X. Qin, Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway. Int J Oncol 48, 1628–1638 (2016)CrossRefPubMedGoogle Scholar
  98. 98.
    Z. Zhang, F. Zheng, Z. Yu, J. Hao, M. Chen, W. Yu, W. Guo, Y. Chen, W. Huang, Z. Duan, W. Deng, XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers. PLoS One 12, e0186900 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    S. Ebrahimi, S.I. Hashemy, MicroRNA-mediated redox regulation modulates therapy resistance in cancer cells: Clinical perspectives. Cell Oncol 42, 131–141 (2019)CrossRefGoogle Scholar
  100. 100.
    C.L. Grek, K.D. Tew, Redox metabolism and malignancy. Curr Opin Pharmacol 10, 362–368 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Z.A. Ibrahim, C.L. Armour, S. Phipps, M.B. Sukkar, RAGE and TLRs: Relatives, friends or neighbours? Mol Immunol 56, 739–744 (2013)CrossRefPubMedGoogle Scholar
  102. 102.
    H. Yang, M. Ochani, J. Li, X. Qiang, M. Tanovic, H.E. Harris, S.M. Susarla, L. Ulloa, H. Wang, R. DiRaimo, C.J. Czura, H. Wang, J. Roth, H.S. Warren, M.P. Fink, M.J. Fenton, U. Andersson, K.J. Tracey, Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A 101, 296–301 (2004)CrossRefPubMedGoogle Scholar
  103. 103.
    J. Li, R. Kokkola, S. Tabibzadeh, R. Yang, M. Ochani, X. Qiang, H.E. Harris, C.J. Czura, H. Wang, L. Ulloa, H. Wang, H.S. Warren, L.L. Moldawer, M.P. Fink, U. Andersson, K.J. Tracey, H. Yang, Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med 9, 37–45 (2003)CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    E. Cerami, J. Gao, U. Dogrusoz, B.E. Gross, S.O. Sumer, B.A. Aksoy, A. Jacobsen, C.J. Byrne, M.L. Heuer, E. Larsson, Y. Antipin, B. Reva, A.P. Goldberg, C. Sander, N. Schultz, The cBio Cancer genomics portal: An open platform for exploring multidimensional Cancer genomics data. Cancer Discov 2, 401–404 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    J. Gao, B.A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S.O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, E. Cerami, C. Sander, N. Schultz, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal Sci Signal (2013). CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  2. 2.Paediatric DepartmentRoyal London HospitalLondonUK

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