雖然腫瘤的形成與免疫細胞和炎症有關，但是免疫系統卻常不如預期般消除癌細胞，反而促進癌症的進展。我們發現癌細胞周邊的巨噬細胞不執行吞噬癌細胞的角色，反而活化促癌相關的訊息傳遞路徑幫助腫瘤生長。我們發現前列腺素E2可以活化腫瘤巨噬細胞中的CCAAT/增強子結合蛋白（CEBPD）並且提高其下游基因五聚環蛋白3（PTX3）的釋放，其具有抑制巨噬細胞的吞噬癌細胞的能力。除了發炎相關細胞激素，我們還發現在腫瘤相關巨噬細胞中的CEBPD會受到抗癌藥活化，例如順鉑和5-氟尿嘧啶，會導致腫瘤侵襲、轉移、抗藥性與增加癌幹原性。我們利用螢光素酶檢測法和DNA結合測定法確定在抗癌藥物的刺激下，PTX3是一種CEBPD反應基因並且有促腫瘤的作用。此外，我們發現原核重組PTX3蛋白的C端與哺乳動物的PTX3有著完全相反的致瘤反應。最後我們建立出RI37胜肽抑制劑，是由原核重組PTX3的C端更進一步縮短改良而來，並利用活體試驗其抗腫瘤的作用，而實驗結果發現 RI37胜肽抑制劑可以用於抑制癌症生長和控制侵襲、轉移和抗藥性癌進展的藥物。我們研究中除了提供PTX3在癌細胞和癌周邊組織之間的相互作用，也利用此論點開發出RI37胜肽抑制劑，其效果能有效降低癌細胞的侵襲、轉移和抗藥性的風險。

Although tumors tend to be associated with immune cells and inflammation, this immune response often fails to eliminate the cancer cells and instead promotes cancer progression. Tumor-associated macrophages fail to phagocytose tumor cells and produce signals that promote cancer progression. Firstly, we found that increase abundance of CCAAT/enhancer binding protein delta (CEBPD) in macrophages in response to prostaglandin E2 can enhance production of pentraxin 3 (PTX3), which suppresses the ability of macrophages to phagocytose tumor cells and benefits cancer progression. In addition to inflammatory cytokines, we determined that activation of CEBPD was responsive to anticancer drugs, such as cisplatin and 5-fluorouracil, in tumor-associated macrophages and contributed to the metastasis, invasion, chemoresistance and stemness of cancer cells. A reporter and in vivo DNA binding assays were used to address whether PTX3 is a CEBPD responsive gene and serves as a protumor role upon anticancer drug treatment. Furthermore, we identified that the C-terminus of prokaryotic recombinant PTX3 protein showed an opposite effect to the mammalian PTX3. Finally, RI37, a peptide inhibitor of PTX3, was narrowed down from C-terminus of prokaryotic recombinant PTX3 and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between tumor and its host. The RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers.

1. Heinrich, E.L., Walser, T.C., Krysan, K., Liclican, E.L., Grant, J.L., Rodriguez, N.L., and Dubinett, S.M. 2012. The inflammatory tumor microenvironment, epithelial mesenchymal transition and lung carcinogenesis. Cancer Microenviron 5:5-18.
2. Sun, Y., Campisi, J., Higano, C., Beer, T.M., Porter, P., Coleman, I., True, L., and Nelson, P.S. 2012. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18:1359-1368.
3. Acharyya, S., Oskarsson, T., Vanharanta, S., Malladi, S., Kim, J., Morris, P.G., Manova-Todorova, K., Leversha, M., Hogg, N., Seshan, V.E., et al. 2012. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150:165-178.
4. Zhu, Y., Knolhoff, B.L., Meyer, M.A., Nywening, T.M., West, B.L., Luo, J., Wang-Gillam, A., Goedegebuure, S.P., Linehan, D.C., and DeNardo, D.G. 2014. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74:5057-5069.
5. Chen, W.J., Ho, C.C., Chang, Y.L., Chen, H.Y., Lin, C.A., Ling, T.Y., Yu, S.L., Yuan, S.S., Chen, Y.J., Lin, C.Y., et al. 2014. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat Commun 5:3472.
6. Paget, S. 1989. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8:98-101.
7. Fidler, I.J. 2003. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3:453-458.
8. Gao, D., Vahdat, L.T., Wong, S., Chang, J.C., and Mittal, V. 2012. Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res 72:4883-4889.
9. Bremnes, R.M., Al-Shibli, K., Donnem, T., Sirera, R., Al-Saad, S., Andersen, S., Stenvold, H., Camps, C., and Busund, L.T. 2011. The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer. J Thorac Oncol 6:824-833.
10. O'Callaghan, D.S., O'Donnell, D., O'Connell, F., and O'Byrne, K.J. 2010. The role of inflammation in the pathogenesis of non-small cell lung cancer. J Thorac Oncol 5:2024-2036.
11. Mantovani, A., Sica, A., and Locati, M. 2005. Macrophage polarization comes of age. Immunity 23:344-346.
12. Cramer, D.W., and Finn, O.J. 2011. Epidemiologic perspective on immune-surveillance in cancer. Curr Opin Immunol 23:265-271.
13. Germano, G., Allavena, P., and Mantovani, A. 2008. Cytokines as a key component of cancer-related inflammation. Cytokine 43:374-379.
14. Gilbert, C.A., and Slingerland, J.M. 2013. Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annu Rev Med 64:45-57.
15. Colotta, F., Allavena, P., Sica, A., Garlanda, C., and Mantovani, A. 2009. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30:1073-1081.
16. Janikashvili, N., Bonnotte, B., Katsanis, E., and Larmonier, N. 2011. The dendritic cell-regulatory T lymphocyte crosstalk contributes to tumor-induced tolerance. Clin Dev Immunol 2011:430394.
17. Joyce, J.A., and Pollard, J.W. 2009. Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239-252.
18. Mercalli, A., Calavita, I., Dugnani, E., Citro, A., Cantarelli, E., Nano, R., Melzi, R., Maffi, P., Secchi, A., Sordi, V., et al. 2013. Rapamycin unbalances the polarization of human macrophages to M1. Immunology 140:179-190.
19. Allavena, P., Sica, A., Solinas, G., Porta, C., and Mantovani, A. 2008. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66:1-9.
20. Sica, A., and Mantovani, A. 2012. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787-795.
21. Condeelis, J., and Pollard, J.W. 2006. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263-266.
22. Pollard, J.W. 2004. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71-78.
23. DeNardo, D.G., Barreto, J.B., Andreu, P., Vasquez, L., Tawfik, D., Kolhatkar, N., and Coussens, L.M. 2009. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91-102.
24. Vermeulen, L., De Sousa, E.M.F., van der Heijden, M., Cameron, K., de Jong, J.H., Borovski, T., Tuynman, J.B., Todaro, M., Merz, C., Rodermond, H., et al. 2010. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12:468-476.
25. Qian, X., Zhang, J., and Liu, J. 2011. Tumor-secreted PGE2 inhibits CCL5 production in activated macrophages through cAMP/PKA signaling pathway. J Biol Chem 286:2111-2120.
26. Yao, M., Ohshima, K., Suzumiya, J., Kume, T., Shiroshita, T., and Kikuchi, M. 1997. Interleukin-10 expression and cytotoxic-T-cell response in Epstein-Barr-virus-associated nasopharyngeal carcinoma. Int J Cancer 72:398-402.
27. Tjiu, J.W., Chen, J.S., Shun, C.T., Lin, S.J., Liao, Y.H., Chu, C.Y., Tsai, T.F., Chiu, H.C., Dai, Y.S., Inoue, H., et al. 2009. Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Invest Dermatol 129:1016-1025.
28. Puig-Kroger, A., Sierra-Filardi, E., Dominguez-Soto, A., Samaniego, R., Corcuera, M.T., Gomez-Aguado, F., Ratnam, M., Sanchez-Mateos, P., and Corbi, A.L. 2009. Folate receptor beta is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory macrophages. Cancer Res 69:9395-9403.
29. Lee, C.H., Yeh, T.H., Lai, H.C., Wu, S.Y., Su, I.J., Takada, K., and Chang, Y. 2011. Epstein-barr virus zta-induced immunomodulators from nasopharyngeal carcinoma cells upregulate interleukin-10 production from monocytes. J Virol 85:7333-7342.
30. de Waal Malefyt, R., Haanen, J., Spits, H., Roncarolo, M.G., te Velde, A., Figdor, C., Johnson, K., Kastelein, R., Yssel, H., and de Vries, J.E. 1991. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 174:915-924.
31. Sakakura, T., Nishizuka, Y., and Dawe, C.J. 1976. Mesenchyme-dependent morphogenesis and epithelium-specific cytodifferentiation in mouse mammary gland. Science 194:1439-1441.
32. Place, A.E., Jin Huh, S., and Polyak, K. 2011. The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res 13:227.
33. Siveen, K.S., and Kuttan, G. 2009. Role of macrophages in tumour progression. Immunol Lett 123:97-102.
34. Sica, A., Larghi, P., Mancino, A., Rubino, L., Porta, C., Totaro, M.G., Rimoldi, M., Biswas, S.K., Allavena, P., and Mantovani, A. 2008. Macrophage polarization in tumour progression. Semin Cancer Biol 18:349-355.
35. Porta, C., Larghi, P., Rimoldi, M., Totaro, M.G., Allavena, P., Mantovani, A., and Sica, A. 2009. Cellular and molecular pathways linking inflammation and cancer. Immunobiology 214:761-777.
36. Zhu, X., Mulcahy, L.A., Mohammed, R.A., Lee, A.H., Franks, H.A., Kilpatrick, L., Yilmazer, A., Paish, E.C., Ellis, I.O., Patel, P.M., et al. 2008. IL-17 expression by breast-cancer-associated macrophages: IL-17 promotes invasiveness of breast cancer cell lines. Breast Cancer Res 10:R95.
37. Hansen, B.D., Schmidt, H., von der Maase, H., Sjoegren, P., Agger, R., and Hokland, M. 2006. Tumour-associated macrophages are related to progression in patients with metastatic melanoma following interleukin-2 based immunotherapy. Acta Oncol 45:400-405.
38. Steidl, C., Lee, T., Shah, S.P., Farinha, P., Han, G., Nayar, T., Delaney, A., Jones, S.J., Iqbal, J., Weisenburger, D.D., et al. 2010. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med 362:875-885.
39. Solinas, G., Germano, G., Mantovani, A., and Allavena, P. 2009. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065-1073.
40. Paik, S., Shak, S., Tang, G., Kim, C., Baker, J., Cronin, M., Baehner, F.L., Walker, M.G., Watson, D., Park, T., et al. 2004. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826.
41. Ma, W.J., Cheng, S., Campbell, C., Wright, A., and Furneaux, H. 1996. Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem 271:8144-8151.
42. Ma, W.J., and Furneaux, H. 1997. Localization of the human HuR gene to chromosome 19p13.2. Hum Genet 99:32-33.
43. Burd, C.G., and Dreyfuss, G. 1994. Conserved structures and diversity of functions of RNA-binding proteins. Science 265:615-621.
44. Ma, W.J., Chung, S., and Furneaux, H. 1997. The Elav-like proteins bind to AU-rich elements and to the poly(A) tail of mRNA. Nucleic Acids Res 25:3564-3569.
45. Lopez de Silanes, I., Zhan, M., Lal, A., Yang, X., and Gorospe, M. 2004. Identification of a target RNA motif for RNA-binding protein HuR. Proc Natl Acad Sci U S A 101:2987-2992.
46. Myer, V.E., Fan, X.C., and Steitz, J.A. 1997. Identification of HuR as a protein implicated in AUUUA-mediated mRNA decay. EMBO J 16:2130-2139.
47. Fan, X.C., and Steitz, J.A. 1998. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J 17:3448-3460.
48. Brennan, C.M., and Steitz, J.A. 2001. HuR and mRNA stability. Cell Mol Life Sci 58:266-277.
49. Kullmann, M., Gopfert, U., Siewe, B., and Hengst, L. 2002. ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5'UTR. Genes Dev 16:3087-3099.
50. Mazan-Mamczarz, K., Galban, S., Lopez de Silanes, I., Martindale, J.L., Atasoy, U., Keene, J.D., and Gorospe, M. 2003. RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation. Proc Natl Acad Sci U S A 100:8354-8359.
51. Kawai, T., Lal, A., Yang, X., Galban, S., Mazan-Mamczarz, K., and Gorospe, M. 2006. Translational control of cytochrome c by RNA-binding proteins TIA-1 and HuR. Mol Cell Biol 26:3295-3307.
52. Balkhi, M.Y., Iwenofu, O.H., Bakkar, N., Ladner, K.J., Chandler, D.S., Houghton, P.J., London, C.A., Kraybill, W., Perrotti, D., Croce, C.M., et al. 2013. miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR. Sci Signal 6:ra63.
53. Sharma, S., Verma, S., Vasudevan, M., Samanta, S., Thakur, J.K., and Kulshreshtha, R. 2013. The interplay of HuR and miR-3134 in regulation of AU rich transcriptome. RNA Biol 10:1283-1290.
54. Yang, F., Miao, L., Mei, Y., and Wu, M. 2013. Retinoic acid-induced HOXA5 expression is co-regulated by HuR and miR-130a. Cell Signal 25:1476-1485.
55. Prislei, S., Martinelli, E., Mariani, M., Raspaglio, G., Sieber, S., Ferrandina, G., Shahabi, S., Scambia, G., and Ferlini, C. 2013. MiR-200c and HuR in ovarian cancer. BMC Cancer 13:72.
56. Zhu, H., Zhou, H.L., Hasman, R.A., and Lou, H. 2007. Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences. J Biol Chem 282:2203-2210.
57. Hinman, M.N., and Lou, H. 2008. Diverse molecular functions of Hu proteins. Cell Mol Life Sci 65:3168-3181.
58. Abdelmohsen, K., Lal, A., Kim, H.H., and Gorospe, M. 2007. Posttranscriptional orchestration of an anti-apoptotic program by HuR. Cell Cycle 6:1288-1292.
59. Yiakouvaki, A., Dimitriou, M., Karakasiliotis, I., Eftychi, C., Theocharis, S., and Kontoyiannis, D.L. 2012. Myeloid cell expression of the RNA-binding protein HuR protects mice from pathologic inflammation and colorectal carcinogenesis. J Clin Invest 122:48-61.
60. Katsanou, V., Papadaki, O., Milatos, S., Blackshear, P.J., Anderson, P., Kollias, G., and Kontoyiannis, D.L. 2005. HuR as a negative posttranscriptional modulator in inflammation. Mol Cell 19:777-789.
61. Nguyen-Chi, M., and Morello, D. 2008. Aberrant regulation of mRNA 3' untranslated region in cancers and inflammation. Med Sci (Paris) 24:290-296.
62. Doller, A., Pfeilschifter, J., and Eberhardt, W. 2008. Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR. Cell Signal 20:2165-2173.
63. Fan, X.C., and Steitz, J.A. 1998. HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc Natl Acad Sci USA 95:15293-15298.
64. Yuan, Z., Sanders, A.J., Ye, L., Wang, Y., and Jiang, W.G. 2011. Knockdown of human antigen R reduces the growth and invasion of breast cancer cells in vitro and affects expression of cyclin D1 and MMP-9. Oncol Rep 26:237-245.
65. Cho, N.P., Han, H.S., Soh, Y., Lee, K.Y., and Son, H.J. 2007. Cytoplasmic HuR over-expression is associated with increased cyclooxygenase-2 expression in laryngeal squamous cell carcinomas. Pathology 39:545-550.
66. Embade, N., Fernandez-Ramos, D., Varela-Rey, M., Beraza, N., Sini, M., de Juan, V.G., Woodhoo, A., Martinez-Lopez, N., Rodriguez-Iruretagoyena, B., Bustamante, F.J., et al. 2011. Mdm2 regulates HuR stability in human liver and colon cancer through neddylation. Hepatology 55:1237-1248.
67. Lopez de Silanes, I., Lal, A., and Gorospe, M. 2005. HuR: post-transcriptional paths to malignancy. RNA Biol 2:11-13.
68. Kotta-Loizou, I., Giaginis, C., and Theocharis, S. 2014. Clinical significance of HuR expression in human malignancy. Med Oncol 31:161.
69. Wu, Z., Bucher, N.L., and Farmer, S.R. 1996. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol Cell Biol 16:4128-4136.
70. Tanaka, T., Yoshida, N., Kishimoto, T., and Akira, S. 1997. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J 16:7432-7443.
71. Scott, L.M., Civin, C.I., Rorth, P., and Friedman, A.D. 1992. A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. Blood 80:1725-1735.
72. Cardinaux, J.R., and Magistretti, P.J. 1996. Vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, and noradrenaline induce the transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and C/EBP delta in mouse cortical astrocytes: involvement in cAMP-regulated glycogen metabolism. J Neurosci 16:919-929.
73. Zannetti, C., Bonnay, F., Takeshita, F., Parroche, P., Menetrier-Caux, C., Tommasino, M., and Hasan, U.A. 2010. C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity. J Biol Chem 285:34773-34780.
74. Ramji, D.P., and Foka, P. 2002. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J 365:561-575.
75. Osada, S., Yamamoto, H., Nishihara, T., and Imagawa, M. 1996. DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family. J Biol Chem 271:3891-3896.
76. Cao, Z., Umek, R.M., and McKnight, S.L. 1991. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev 5:1538-1552.
77. Wang, W.L., Lee, Y.C., Yang, W.M., Chang, W.C., and Wang, J.M. 2008. Sumoylation of LAP1 is involved in the HDAC4-mediated repression of COX-2 transcription. Nucleic Acids Res 36:6066-6079.
78. Xia, C., Cheshire, J.K., Patel, H., and Woo, P. 1997. Cross-talk between transcription factors NF-kappa B and C/EBP in the transcriptional regulation of genes. Int J Biochem Cell Biol 29:1525-1539.
79. Ji, C., Chang, W., Centrella, M., and McCarthy, T.L. 2003. Activation domains of CCAAT enhancer binding protein delta: regions required for native activity and prostaglandin E2-dependent transactivation of insulin-like growth factor I gene expression in rat osteoblasts. Mol Endocrinol 17:1834-1843.
80. Okazaki, K., Li, J., Yu, H., Fukui, N., and Sandell, L.J. 2002. CCAAT/enhancer-binding proteins beta and delta mediate the repression of gene transcription of cartilage-derived retinoic acid-sensitive protein induced by interleukin-1 beta. J Biol Chem 277:31526-31533.
81. Wu, S.R., Li, C.F., Hung, L.Y., Huang, A.M., Tseng, J.T., Tsou, J.H., and Wang, J.M. 2011. CCAAT/enhancer-binding protein delta mediates tumor necrosis factor alpha-induced Aurora kinase C transcription and promotes genomic instability. J Biol Chem 286:28662-28670.
82. Balamurugan, K., and Sterneck, E. 2013. The many faces of C/EBPdelta and their relevance for inflammation and cancer. Int J Biol Sci 9:917-933.
83. Sato, Y., Nishio, Y., Sekine, O., Kodama, K., Nagai, Y., Nakamura, T., Maegawa, H., and Kashiwagi, A. 2007. Increased expression of CCAAT/enhancer binding protein-beta and -delta and monocyte chemoattractant protein-1 genes in aortas from hyperinsulinaemic rats. Diabetologia 50:481-489.
84. Hsiao, Y.W., Li, C.F., Chi, J.Y., Tseng, J.T., Chang, Y., Hsu, L.J., Lee, C.H., Chang, T.H., Wang, S.M., Wang, D.D., et al. 2013. CCAAT/enhancer binding protein delta in macrophages contributes to immunosuppression and inhibits phagocytosis in nasopharyngeal carcinoma. Sci Signal 6:ra59.
85. Ko, C.Y., Hsu, H.C., Shen, M.R., Chang, W.C., and Wang, J.M. 2008. Epigenetic silencing of CCAAT/enhancer-binding protein delta activity by YY1/polycomb group/DNA methyltransferase complex. J Biol Chem 283:30919-30932.
86. Balamurugan, K., Wang, J.M., Tsai, H.H., Sharan, S., Anver, M., Leighty, R., and Sterneck, E. 2010. The tumour suppressor C/EBPdelta inhibits FBXW7 expression and promotes mammary tumour metastasis. EMBO J 29:4106-4117.
87. Garlanda, C., Bottazzi, B., Bastone, A., and Mantovani, A. 2005. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 23:337-366.
88. Mantovani, A., Garlanda, C., Doni, A., and Bottazzi, B. 2008. Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol 28:1-13.
89. Peri, G., Introna, M., Corradi, D., Iacuitti, G., Signorini, S., Avanzini, F., Pizzetti, F., Maggioni, A.P., Moccetti, T., Metra, M., et al. 2000. PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans. Circulation 102:636-641.
90. Salio, M., Chimenti, S., De Angelis, N., Molla, F., Maina, V., Nebuloni, M., Pasqualini, F., Latini, R., Garlanda, C., and Mantovani, A. 2008. Cardioprotective function of the long pentraxin PTX3 in acute myocardial infarction. Circulation 117:1055-1064.
91. Bonacina, F., Baragetti, A., Catapano, A.L., and Norata, G.D. 2013. Long pentraxin 3: experimental and clinical relevance in cardiovascular diseases. Mediators Inflamm 2013:725102.
92. Sardana, G., Jung, K., Stephan, C., and Diamandis, E.P. 2008. Proteomic analysis of conditioned media from the PC3, LNCaP, and 22Rv1 prostate cancer cell lines: discovery and validation of candidate prostate cancer biomarkers. J Proteome Res 7:3329-3338.
93. Diamandis, E.P., Goodglick, L., Planque, C., and Thornquist, M.D. 2011. Pentraxin-3 is a novel biomarker of lung carcinoma. Clin Cancer Res 17:2395-2399.
94. Altmeyer, A., Klampfer, L., Goodman, A.R., and Vilcek, J. 1995. Promoter structure and transcriptional activation of the murine TSG-14 gene encoding a tumor necrosis factor/interleukin-1-inducible pentraxin protein. J Biol Chem 270:25584-25590.
95. Inforzato, A., Reading, P.C., Barbati, E., Bottazzi, B., Garlanda, C., and Mantovani, A. 2012. The "sweet" side of a long pentraxin: how glycosylation affects PTX3 functions in innate immunity and inflammation. Front Immunol 3:407.
96. Inforzato, A., Rivieccio, V., Morreale, A.P., Bastone, A., Salustri, A., Scarchilli, L., Verdoliva, A., Vincenti, S., Gallo, G., Chiapparino, C., et al. 2008. Structural characterization of PTX3 disulfide bond network and its multimeric status in cumulus matrix organization. J Biol Chem 283:10147-10161.
97. Stallone, G., Cormio, L., Netti, G.S., Infante, B., Selvaggio, O., Fino, G.D., Ranieri, E., Bruno, F., Prattichizzo, C., Sanguedolce, F., et al. 2014. Pentraxin 3: a novel biomarker for predicting progression from prostatic inflammation to prostate cancer. Cancer Res 74:4230-4238.
98. Germano, G., Frapolli, R., Simone, M., Tavecchio, M., Erba, E., Pesce, S., Pasqualini, F., Grosso, F., Sanfilippo, R., Casali, P.G., et al. 2010. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 70:2235-2244.
99. Lu, Y.C., Kim, I., Lye, E., Shen, F., Suzuki, N., Suzuki, S., Gerondakis, S., Akira, S., Gaffen, S.L., Yeh, W.C., et al. 2009. Differential role for c-Rel and C/EBPbeta/delta in TLR-mediated induction of proinflammatory cytokines. J Immunol 182:7212-7221.
100. Ko, C.Y., Chang, L.H., Lee, Y.C., Sterneck, E., Cheng, C.P., Chen, S.H., Huang, A.M., Tseng, J.T., and Wang, J.M. 2012. CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3 expression inhibits macrophage-mediated phagocytosis of dying neuron cells. Neurobiol Aging 33:422 e411-425.
101. Liu, Y.W., Tseng, H.P., Chen, L.C., Chen, B.K., and Chang, W.C. 2003. Functional cooperation of simian virus 40 promoter factor 1 and CCAAT/enhancer-binding protein beta and delta in lipopolysaccharide-induced gene activation of IL-10 in mouse macrophages. J Immunol 171:821-828.
102. Yi, J., Chang, N., Liu, X., Guo, G., Xue, L., Tong, T., Gorospe, M., and Wang, W. 2010. Reduced nuclear export of HuR mRNA by HuR is linked to the loss of HuR in replicative senescence. Nucleic Acids Res 38:1547-1558.
103. Liao, H., Hyman, M.C., Baek, A.E., Fukase, K., and Pinsky, D.J. 2010. cAMP/CREB-mediated transcriptional regulation of ectonucleoside triphosphate diphosphohydrolase 1 (CD39) expression. J Biol Chem 285:14791-14805.
104. Chang, L.H., Huang, H.S., Wu, P.T., Jou, I.M., Pan, M.H., Chang, W.C., Wang, D.D., and Wang, J.M. 2012. Role of macrophage CCAAT/enhancer binding protein delta in the pathogenesis of rheumatoid arthritis in collagen-induced arthritic mice. PLoS One 7:e45378.
105. Inforzato, A., Bottazzi, B., Garlanda, C., Valentino, S., and Mantovani, A. 2012. Pentraxins in humoral innate immunity. Adv Exp Med Biol 946:1-20.
106. Chiang, B.T., Liu, Y.W., Chen, B.K., Wang, J.M., and Chang, W.C. 2006. Direct interaction of C/EBPdelta and Sp1 at the GC-enriched promoter region synergizes the IL-10 gene transcription in mouse macrophage. J Biomed Sci 13:621-635.
107. Thomas, B., Berenbaum, F., Humbert, L., Bian, H., Bereziat, G., Crofford, L., and Olivier, J.L. 2000. Critical role of C/EBPdelta and C/EBPbeta factors in the stimulation of the cyclooxygenase-2 gene transcription by interleukin-1beta in articular chondrocytes. Eur J Biochem 267:6798-6809.
108. Nishioka, K., Ohshima, S., Umeshita-Sasai, M., Yamaguchi, N., Mima, T., Nomura, S., Murata, N., Shimizu, M., Miyake, T., Yoshizaki, K., et al. 2000. Enhanced expression and DNA binding activity of two CCAAT/enhancer-binding protein isoforms, C/EBPbeta and C/EBPdelta, in rheumatoid synovium. Arthritis Rheum 43:1591-1596.
109. Rovere, P., Peri, G., Fazzini, F., Bottazzi, B., Doni, A., Bondanza, A., Zimmermann, V.S., Garlanda, C., Fascio, U., Sabbadini, M.G., et al. 2000. The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells. Blood 96:4300-4306.
110. DeNardo, D.G., Brennan, D.J., Rexhepaj, E., Ruffell, B., Shiao, S.L., Madden, S.F., Gallagher, W.M., Wadhwani, N., Keil, S.D., Junaid, S.A., et al. 2011. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1:54-67.
111. Shree, T., Olson, O.C., Elie, B.T., Kester, J.C., Garfall, A.L., Simpson, K., Bell-McGuinn, K.M., Zabor, E.C., Brogi, E., and Joyce, J.A. 2011. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 25:2465-2479.
112. Gilbert, L.A., and Hemann, M.T. 2010. DNA damage-mediated induction of a chemoresistant niche. Cell 143:355-366.
113. Lotti, F., Jarrar, A.M., Pai, R.K., Hitomi, M., Lathia, J., Mace, A., Gantt, G.A., Jr., Sukhdeo, K., DeVecchio, J., Vasanji, A., et al. 2013. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med 210:2851-2872.
114. Deban, L., Russo, R.C., Sironi, M., Moalli, F., Scanziani, M., Zambelli, V., Cuccovillo, I., Bastone, A., Gobbi, M., Valentino, S., et al. 2010. Regulation of leukocyte recruitment by the long pentraxin PTX3. Nat Immunol 11:328-334.
115. Fan, J., Heller, N.M., Gorospe, M., Atasoy, U., and Stellato, C. 2005. The role of post-transcriptional regulation in chemokine gene expression in inflammation and allergy. Eur Respir J 26:933-947.
116. Basu, S.K., Malik, R., Huggins, C.J., Lee, S., Sebastian, T., Sakchaisri, K., Quinones, O.A., Alvord, W.G., and Johnson, P.F. 2011. 3'UTR elements inhibit Ras-induced C/EBPbeta post-translational activation and senescence in tumour cells. EMBO J 30:3714-3728.
117. Galban, S., Kuwano, Y., Pullmann, R., Jr., Martindale, J.L., Kim, H.H., Lal, A., Abdelmohsen, K., Yang, X., Dang, Y., Liu, J.O., et al. 2008. RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha. Mol Cell Biol 28:93-107.
118. Diaz-Munoz, M.D., Osma-Garcia, I.C., Fresno, M., and Iniguez, M.A. 2012. Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. Biochem J 443:451-461.
119. Costantino, C.L., Witkiewicz, A.K., Kuwano, Y., Cozzitorto, J.A., Kennedy, E.P., Dasgupta, A., Keen, J.C., Yeo, C.J., Gorospe, M., and Brody, J.R. 2009. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res 69:4567-4572.
120. McAllister, F., Pineda, D.M., Jimbo, M., Lal, S., Burkhart, R.A., Moughan, J., Winter, K.A., Abdelmohsen, K., Gorospe, M., Acosta Ade, J., et al. 2014. dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: a dual-institutional follow-up with the RTOG 9704 trial. Cancer Biol Ther 15:688-698.
121. Lal, S., Burkhart, R.A., Beeharry, N., Bhattacharjee, V., Londin, E.R., Cozzitorto, J.A., Romeo, C., Jimbo, M., Norris, Z.A., Yeo, C.J., et al. 2014. HuR posttranscriptionally regulates WEE1: implications for the DNA damage response in pancreatic cancer cells. Cancer Res 74:1128-1140.
122. Tsai, V.W., Mohammad, M.G., Tolhurst, O., Breit, S.N., Sawchenko, P.E., and Brown, D.A. 2011. CCAAT/enhancer binding protein-delta expression by dendritic cells regulates CNS autoimmune inflammatory disease. J Neurosci 31:17612-17621.
123. Ko, C.Y., Chang, L.H., Lee, Y.C., Sterneck, E., Cheng, C.P., Chen, S.H., Huang, A.M., Tseng, J.T., and Wang, J.M. 2012 CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3 expression inhibits macrophage-mediated phagocytosis of dying neuron cells. Neurobiol Aging 33:422.e411-425.
124. Baruah, P., Dumitriu, I.E., Peri, G., Russo, V., Mantovani, A., Manfredi, A.A., and Rovere-Querini, P. 2006. The tissue pentraxin PTX3 limits C1q-mediated complement activation and phagocytosis of apoptotic cells by dendritic cells. J Leukoc Biol 80:87-95.
125. Chen, J.J., Lin, Y.C., Yao, P.L., Yuan, A., Chen, H.Y., Shun, C.T., Tsai, M.F., Chen, C.H., and Yang, P.C. 2005. Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 23:953-964.
126. Kaler, P., Galea, V., Augenlicht, L., and Klampfer, L. 2010. Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells. PLoS One 5:e11700.
127. Pan, Y.C., Li, C.F., Ko, C.Y., Pan, M.H., Chen, P.J., Tseng, J.T., Wu, W.C., Chang, W.C., Huang, A.M., Sterneck, E., et al. 2010. CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells. Clin Cancer Res 16:5770-5780.
128. Hour, T.C., Lai, Y.L., Kuan, C.I., Chou, C.K., Wang, J.M., Tu, H.Y., Hu, H.T., Lin, C.S., Wu, W.J., Pu, Y.S., et al. 2010. Transcriptional up-regulation of SOD1 by CEBPD: a potential target for cisplatin resistant human urothelial carcinoma cells. Biochem Pharmacol 80:325-334.
129. Weinstein, P.S., Skinner, M., Sipe, J.D., Lokich, J.J., Zamcheck, N., and Cohen, A.S. 1984. Acute-phase proteins or tumour markers: the role of SAA, SAP, CRP and CEA as indicators of metastasis in a broad spectrum of neoplastic diseases. Scand J Immunol 19:193-198.
130. Yang, J., Wezeman, M., Zhang, X., Lin, P., Wang, M., Qian, J., Wan, B., Kwak, L.W., Yu, L., and Yi, Q. 2007. Human C-reactive protein binds activating Fcgamma receptors and protects myeloma tumor cells from apoptosis. Cancer Cell 12:252-265.
131. Lu, J., Marnell, L.L., Marjon, K.D., Mold, C., Du Clos, T.W., and Sun, P.D. 2008. Structural recognition and functional activation of FcgammaR by innate pentraxins. Nature 456:989-992.
132. Moalli, F., Doni, A., Deban, L., Zelante, T., Zagarella, S., Bottazzi, B., Romani, L., Mantovani, A., and Garlanda, C. 2010. Role of complement and Fc{gamma} receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus. Blood 116:5170-5180.
133. Chen, W.Y., Wu, F., You, Z.Y., Zhang, Z.M., Guo, Y.L., and Zhong, L.X. 2015. Analyzing the differentially expressed genes and pathway cross-talk in aggressive breast cancer. J Obstet Gynaecol Res 41:132-140.
134. Boero, S., Morabito, A., Banelli, B., Cardinali, B., Dozin, B., Lunardi, G., Piccioli, P., Lastraioli, S., Carosio, R., Salvi, S., et al. 2015. Analysis of in vitro ADCC and clinical response to trastuzumab: possible relevance of FcgammaRIIIA/FcgammaRIIA gene polymorphisms and HER-2 expression levels on breast cancer cell lines. J Transl Med 13:324.
135. Menyhart, O., Santarpia, L., and Gyorffy, B. 2015. A Comprehensive Outline of Trastuzumab Resistance Biomarkers in HER2 Overexpressing Breast Cancer. Curr Cancer Drug Targets 15:665-683.
136. Baselga, J., Cortes, J., Im, S.A., Clark, E., Ross, G., Kiermaier, A., and Swain, S.M. 2014. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol 32:3753-3761.
137. Wang, J.X., He, Y.L., Zhu, S.T., Yang, S., and Zhang, S.T. 2011. Aberrant methylation of the 3q25 tumor suppressor gene PTX3 in human esophageal squamous cell carcinoma. World J Gastroenterol 17:4225-4230.
138. Bonavita, E., Gentile, S., Rubino, M., Maina, V., Papait, R., Kunderfranco, P., Greco, C., Feruglio, F., Molgora, M., Laface, I., et al. 2015. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160:700-714.
139. Kondo, S., Ueno, H., Hosoi, H., Hashimoto, J., Morizane, C., Koizumi, F., Tamura, K., and Okusaka, T. 2013. Clinical impact of pentraxin family expression on prognosis of pancreatic carcinoma. Br J Cancer 109:739-746.
140. Choi, B., Lee, E.J., Song, D.H., Yoon, S.C., Chung, Y.H., Jang, Y., Kim, S.M., Song, Y., Kang, S.W., Yoon, S.Y., et al. 2014. Elevated Pentraxin 3 in bone metastatic breast cancer is correlated with osteolytic function. Oncotarget 5:481-492.
141. Chang, W.C., Wu, S.L., Huang, W.C., Hsu, J.Y., Chan, S.H., Wang, J.M., Tsai, J.P., and Chen, B.K. 2015. PTX3 gene activation in EGF-induced head and neck cancer cell metastasis. Oncotarget 6:7741-7757.
142. Choi, B., Lee, E.J., Park, Y.S., Kim, S.M., Kim, E.Y., Song, Y., Kang, S.W., Rhu, M.H., and Chang, E.J. 2015. Pentraxin-3 Silencing Suppresses Gastric Cancer-related Inflammation by Inhibiting Chemotactic Migration of Macrophages. Anticancer Res 35:2663-2668.
143. Ying, T.H., Lee, C.H., Chiou, H.L., Yang, S.F., Lin, C.L., Hung, C.H., Tsai, J.P., and Hsieh, Y.H. 2016. Knockdown of Pentraxin 3 suppresses tumorigenicity and metastasis of human cervical cancer cells. Sci Rep 6:29385.
144. Tung, J.N., Ko, C.P., Yang, S.F., Cheng, C.W., Chen, P.N., Chang, C.Y., Lin, C.L., Yang, T.F., Hsieh, Y.H., and Chen, K.C. 2016. Inhibition of pentraxin 3 in glioma cells impairs proliferation and invasion in vitro and in vivo. J Neurooncol.
145. Chi, J.Y., Hsiao, Y.W., Li, C.F., Lo, Y.C., Lin, Z.Y., Hong, J.Y., Liu, Y.M., Han, X., Wang, S.M., Chen, B.K., et al. 2015. Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers. Oncotarget 6:23987-24001.
146. Magrini, E., Mantovani, A., and Garlanda, C. 2016. The Dual Complexity of PTX3 in Health and Disease: A Balancing Act? Trends Mol Med 22:497-510.
147. Planque, C., Kulasingam, V., Smith, C.R., Reckamp, K., Goodglick, L., and Diamandis, E.P. 2009. Identification of five candidate lung cancer biomarkers by proteomics analysis of conditioned media of four lung cancer cell lines. Mol Cell Proteomics 8:2746-2758.
148. Willeke, F., Assad, A., Findeisen, P., Schromm, E., Grobholz, R., von Gerstenbergk, B., Mantovani, A., Peri, S., Friess, H.H., Post, S., et al. 2006. Overexpression of a member of the pentraxin family (PTX3) in human soft tissue liposarcoma. Eur J Cancer 42:2639-2646.
149. Pavlou, M.P., Dimitromanolakis, A., and Diamandis, E.P. 2013. Coupling proteomics and transcriptomics in the quest of subtype-specific proteins in breast cancer. Proteomics 13:1083-1095.
150. Locatelli, M., Ferrero, S., Martinelli Boneschi, F., Boiocchi, L., Zavanone, M., Maria Gaini, S., Bello, L., Valentino, S., Barbati, E., Nebuloni, M., et al. 2013. The long pentraxin PTX3 as a correlate of cancer-related inflammation and prognosis of malignancy in gliomas. J Neuroimmunol 260:99-106.
151. Ronca, R., Giacomini, A., Di Salle, E., Coltrini, D., Pagano, K., Ragona, L., Matarazzo, S., Rezzola, S., Maiolo, D., Torrella, R., et al. 2015. Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy. Cancer Cell 28:225-239.
152. Ronca, R., Alessi, P., Coltrini, D., Di Salle, E., Giacomini, A., Leali, D., Corsini, M., Belleri, M., Tobia, C., Garlanda, C., et al. 2013. Long pentraxin-3 as an epithelial-stromal fibroblast growth factor-targeting inhibitor in prostate cancer. J Pathol 230:228-238.
153. Rusnati, M., Camozzi, M., Moroni, E., Bottazzi, B., Peri, G., Indraccolo, S., Amadori, A., Mantovani, A., and Presta, M. 2004. Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis. Blood 104:92-99.
154. Falasca M, B.F., Catapano AL, Norata GD. 2013. The Long Pentraxin PTX3: A Biomarker Spanning From Cardiovascular Disorders to Cancer. J Mol Biomark Diagn 4:1-3.
155. Leali, D., Inforzato, A., Ronca, R., Bianchi, R., Belleri, M., Coltrini, D., Di Salle, E., Sironi, M., Norata, G.D., Bottazzi, B., et al. 2012. Long pentraxin 3/tumor necrosis factor-stimulated gene-6 interaction: a biological rheostat for fibroblast growth factor 2-mediated angiogenesis. Arterioscler Thromb Vasc Biol 32:696-703.