Interleukin-12 inhibits the hepatocellular carcinoma growth by inducing macrophage polarization to the M1-like phenotype through downregulation of Stat-3

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• 作者：Qin Wang ; Feng Cheng ; Ting-ting Ma ; Hai-Yu Xiong…
• 关键词：IL ; 12 ; CD197 ; CD206 ; Hepatocellular carcinoma ; M1 macrophages
• 刊名：Molecular and Cellular Biochemistry
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：415
• 期：1-2
• 页码：157-168
• 全文大小：3,033 KB
• 参考文献：1.Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907–1917CrossRef PubMed
  2.Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRef PubMed
  3.Shirabe K, Kanematsu T, Matsumata T et al (1991) Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate and multivariate analyses. Hepatology 14:802–805CrossRef PubMed
  4.Yamashita Y, Morita K, Iguchi T et al (2011) Surgical impacts of an en bloc resection of the diaphragm for hepatocellular carcinoma with gross diaphragmatic involvement. Surg Today 41:101–106CrossRef PubMed
  5.Sakaguchi T, Suzuki S, Morita Y et al (2010) Impact of the preoperative des-gamma-carboxy prothrombin level on prognosis after hepatectomy for hepatocellular carcinoma meeting the Milan criteria. Surg Today 40:638–645CrossRef PubMed
  6.Taketomi A, Fukuhara T, Morita K et al (2010) Improved results of a surgical resection for the recurrence of hepatocellular carcinoma after living donor liver transplantation. Ann Surg Oncol 17:2283–2289CrossRef PubMed
  7.de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37CrossRef PubMed
  8.Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612CrossRef PubMed
  9.Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795CrossRef PubMed PubMedCentral
  10.Porta C, Riboldi E, Totaro MG et al (2011) Macrophages in cancer and infectious diseases: the ‘good’ and the ‘bad’. Immunotherapy 3:1185–1202CrossRef PubMed
  11.Baay M, Brouwer A, Pauwels P et al (2011) Tumor cells and tumor-associated macrophages: secreted proteins as potential targets for therapy. Clin Dev Immunol 2011:565187CrossRef PubMed PubMedCentral
  12.Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796:11–18PubMed
  13.Satoh T, Saika T, Ebara S et al (2003) Macrophages transduced with an adenoviral vector expressing interleukin 12 suppress tumor growth and metastasis in a preclinical metastatic prostate cancer model. Cancer Res 63:7853–7860PubMed
  14.Chehimi J, Trinchieri G (1994) Interleukin-12: a bridge between innate resistance and adaptive immunity with a role in infection and acquired immunodeficiency. J Clin Immunol 14:149–161CrossRef PubMed
  15.Beadling C, Slifka MK (2006) Regulation of innate and adaptive immune responses by the related cytokines IL-12, IL-23, and IL-27. Arch Immunol Ther Exp 54:15–24CrossRef
  16.Del Vecchio M, Bajetta E, Canova S et al (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677–4685CrossRef PubMed
  17.Hamza T, Barnett JB, Li B (2010) Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci 11:789–806CrossRef PubMed PubMedCentral
  18.Tatsumi T, Huang J, Gooding WE et al (2003) Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity. Cancer Res 63:6378–6386PubMed
  19.Watkins SK, Egilmez NK, Suttles J et al (2007) IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol 178:1357–1362CrossRef PubMed
  20.Ma TT, Wu BT, Lin Y et al (2015) IL-12 could induce monocytic tumor cells directional differentiation. Mol Cell Biochem 402:157–169CrossRef PubMed
  21.Cheng F, Kuang WB, Wang Q et al (2012) construction of adenovirus vector containning hIL-12 gene and its effects on the proliferation and TGF- expression of Hep3B cells. Chin J Immunol 28:402–406
  22.Davies JQ, Gordon S (2005) Isolation and culture of human macrophages. Methods Mol Biol 290:105–116PubMed
  23.Wermuth PJ, Del Galdo F, Jiménez SA (2009) Induction of the expression of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents. Arthritis Rheum 60:1508–1518CrossRef PubMed PubMedCentral
  24.Zhou JR, Yu L, Mai Z et al (2004) Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice. Int J Cancer 108:8–14CrossRef PubMed PubMedCentral
  25.Zhou JR, Mukherjee P, Gugger ET et al (1998) Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis. Cancer Res 58:5231–5238PubMed
  26.Kuwai T, Kitadai Y, Tanaka S et al (2003) Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma. Int J Cancer 105:176–181CrossRef PubMed
  27.Mantovani A, Biswas SK, Galdiero MR et al (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–185CrossRef PubMed
  28.Allavena P, Sica A, Solinas G et al (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66:1–9CrossRef PubMed
  29.Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964CrossRef PubMed
  30.Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483CrossRef PubMed
  31.Vicari AP, Chiodoni C, Vaure C et al (2002) Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin10 receptor antibody. J Exp Med 196:541–549CrossRef PubMed PubMedCentral
  32.Barrios B, Baez NS, Reynolds D et al (2014) Abrogation of TNFα production during cancer immunotherapy is crucial for suppressing side effects due to the systemic expression of IL-12. PLoS One 9:e90116CrossRef PubMed PubMedCentral
  33.Bai J, Adriani G, Dang TM et al (2015) Contact-dependent carcinoma aggregate dispersion by M2a macrophages via ICAM-1 and β2 integrin interactions. Oncotarget 6:25295–25307CrossRef PubMed PubMedCentral
  34.Genin M, Clement F, Fattaccioli A et al (2015) M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer 15:577CrossRef PubMed PubMedCentral
  35.Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795CrossRef PubMed PubMedCentral
  36.Solinas G, Germano G, Mantovani A et al (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065–1073CrossRef PubMed
  37.Ugel S, Delpozzo F, Desantis G et al (2009) Therapeutic targeting of myeloid-derived suppressor cells. Curr Opin Pharmacol 9:470–841CrossRef PubMed
  38.Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117:1155–1166CrossRef PubMed PubMedCentral
  39.Wan S, Zhao E, Kryczek I et al (2014) Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147:1393–1404CrossRef PubMed PubMedCentral
  40.Mano Y, Aishima S, Fujita N et al (2013) Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma. Pathobiology 80:146–154CrossRef PubMed
  41.Zhou N, Zhang Y, Zhang X et al (2015) Exposure of tumor-associated macrophages to apoptotic MCF-7 cells promotes breast cancer growth and metastasis. Int J Mol Sci 16:11966–11982CrossRef PubMed PubMedCentral
  42.Pello OM, De Pizzol M, Mirolo M et al (2012) Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood 119:411–421CrossRef PubMed
  
• 作者单位：Qin Wang (1)
  Feng Cheng (1)
  Ting-ting Ma (1)
  Hai-Yu Xiong (1)
  Zi-Wei Li (1)
  Chang-Li Xie (1)
  Cui-Ying Liu (1)
  Zhi-Guang Tu (1)
  
  1. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Medical Biochemistry
  Oncology
  Cardiology
  
• 出版者：Springer Netherlands
• ISSN：1573-4919

文摘

Hepatocellular carcinoma is the third most common cause of cancer death worldwide. Novel early detection biomarkers and efficacious therapy strategies are needed. Macrophages recruited from circulation monocytes are the major component of solid cancer and play an important role in the carcinogenesis. Whether overexpression of L-12 in monocytes could induce the phenotype directional differentiation into tumoricidal M1 macrophages and inhibit HCC growth in tumor microenvironment was investigated in this study. For the establishment of the monocyte/IL-12 and polarization of M1-like macrophage, the IL-12 overexpressing recombinant monocyte/IL-12 cells were established by infecting with pAd5F35-CMV/IL-12 adenovirus and co-cultured with HCC SMMC-7721 and Hep3B cells. It was found that the phenotype of monocyte/IL-12 polarized to M1-like macrophages with CD197high IL-12high CD206low IL-10low, and decreased expression of TGF-β, VEGF-A, and MMP-9. In order to explore the mechanism underlying the macrophages polarization, we detected the Stat-3 pathway and its downstream transcription factor c-myc, and found that the p-Stat-3 and c-myc were down-regulated. To evaluate the effects of monocyte/IL-12 on inhibiting HCC growth, various assays including CCK8, flow cytometry, colony-forming and Transwell assays in vitro, and xenograft mouse models and immunohistochemical analyses in vivo were used to detect the HCC growth and relative markers. Treated with IL-12 overexpressing monocytes, the xenograft tumor growth was significantly inhibited in vivo. These results have proven that IL-12-overexpressed monocytes could directionally differentiate to M1-like macrophages through downregulation of Stat-3 and result in the inhibition of HCC growth.