抑制巨噬细胞Act 1表达对黑色素瘤肺转移的影响
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摘要
目的本文通过建立黑色素瘤肺转移模型,研究巨噬细胞NF-κB活化因子1(nuclear factor kappa B activator 1,Act 1)对黑色素瘤肺转移的影响。方法以抑制巨噬细胞Act 1表达的小鼠(anti-Act 1)为研究对象,通过尾静脉注射B16-F10细胞诱导肺转移模型,采用HE染色法检测小鼠肺组织的转移情况;免疫组化方法分析肿瘤细胞的增殖指数和白细胞、巨噬细胞的浸润情况。结果与C57小鼠相比,在尾静脉注射B16-F10细胞20 d后,实验组anti-Act 1小鼠肺组织转移灶面积、数量较少;Ki67、CD45、CD68表达量较低。结论靶向抑制巨噬细胞Act 1表达能够显著减轻黑色素瘤肺转移程度。
Objective To investigate the effects of nuclear factor kappa B activator 1(Act1) on lung metastasis of melanoma in mice.Methods Mice were genetically engineered to enable the targeted suppression of Act1 in macrophages(anti-Act1).The lung metastasis model was generated by tail vein injection of B16-F10 melanoma cells.The extent of lung metastasis was assessed pathology using HE staining of lung tissues.The infiltration of CD45+leukocytes and CD68+macrophages and the proliferation index of tumor cells in lung tissues were evaluated by immunohistochemistry.Results The anti-Act1 mice developed fewer metastatic and micro-metastatic foci,with reduced CD45+leukocyte and CD68+macrophage infiltration in the lung tissues,when compared with the C57 control mice.Cells of metastatic and micro-metastatic foci in the anti-Act1 mice demonstrated a reduced proliferation index,when compared with those of control animals.Conclusions Targeted suppression of Act1 in macrophages inhibits the lung metastasis of murine melanoma.
Objective To investigate the effects of nuclear factor kappa B activator 1(Act1) on lung metastasis of melanoma in mice.Methods Mice were genetically engineered to enable the targeted suppression of Act1 in macrophages(anti-Act1).The lung metastasis model was generated by tail vein injection of B16-F10 melanoma cells.The extent of lung metastasis was assessed pathology using HE staining of lung tissues.The infiltration of CD45+leukocytes and CD68+macrophages and the proliferation index of tumor cells in lung tissues were evaluated by immunohistochemistry.Results The anti-Act1 mice developed fewer metastatic and micro-metastatic foci,with reduced CD45+leukocyte and CD68+macrophage infiltration in the lung tissues,when compared with the C57 control mice.Cells of metastatic and micro-metastatic foci in the anti-Act1 mice demonstrated a reduced proliferation index,when compared with those of control animals.Conclusions Targeted suppression of Act1 in macrophages inhibits the lung metastasis of murine melanoma.
引文
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[18]李艺丹.第一部分:核定位Act1介导组蛋白H3第14位赖氨酸乙酰化和组织因子的转录调控;第二部分:穿心莲内酯(Andro)抗炎与抗血栓机制的研究[D],2009.
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[2]Inoue T,Cavanaugh PG,Steck PA,et al.Differences in transferrin response and numbers of transferrin receptors in rat and human mammary carcinoma lines of different metastatic potentials[J].J Cell Physiol,1993,156(1):212-217.
[3]朱莺娇,赖晓兰,赵珅,et al.CB6F1小鼠黑色素瘤B16-F10细胞移植瘤模型的建立[J].肿瘤研究与临床,2015,27(5):316-319.
[4]Hui L,Chen Y.Tumor microenvironment:Sanctuary of the devil[J].Cancer Lett,2015,368(1):7-13.
[5]Ansell SM,Vonderheide RH.Cellular composition of the tumor microenvironment[J].Am Soc Clin Oncol Educ Book,2013,33:91.
[6]Qian F,Engst S,Yamaguchi K,et al.Inhibition of tumor cell growth,invasion,and metastasis by EXEL-2880(XL880,GSK1363089),a novel inhibitor of HGF and VEGF receptor tyrosine kinases[J].Cancer Res,2009,69(20):8009-8016.
[7]De Palma M,Biziato D,Petrova TV.Microenvironmental regulation of tumour angiogenesis[J].Nat Rev Cancer,2017,17(8):457-474.
[8]Wu P,Wu D,Zhao L,et al.Inverse role of distinct subsets and distribution of macrophage in lung cancer prognosis:a metaanalysis[J].Oncotarget,2016,7(26):40451-40460.
[9]Zhou K,Yan Y,Zhao S,et al.Clinical application and prognostic assessment of serum Tumor Associated Material(TAM)from esophageal cancer patients[J].Eur Rev Med Pharmacol Sci,2014,18(24):3870-3876.
[10]Li X,Commane M,Nie H,et al.Act1,an NF-kappa B-activating protein[J].Proc Natl Acad Sci USA,2000,97(19):10489-10493.
[11]Oeckinghaus A,Hayden MS,Ghosh S.Crosstalk in NF-κBsignaling pathways[J].Nat Immunol,2011,12(8):695-708.
[12]Ben-Neriah Y,Karin M.Inflammation meets cancer,with NF-kappaB as the matchmaker[J].Nat Immunol,2011,12(8):715-723.
[13]Chaturvedi MM,Sung B,Yadav VR,et al.NF-kappaBaddiction and its role in cancer:‘one size does not fit all’[J].Oncogene,2011,30(14):1615-1630.
[14]Welte T,Zhang XHF.Interleukin-17 could promote breast cancer progression at several states of the disease[J].Mediators Inflamm,2015,2015:804347.
[15]Goldstein RH,Reagan MR,Anderson K,et al.Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis[J].Cancer Res,2010,70(24):10044-10050.
[16]Chang SH,Park H,Dong C.Act1 adaptor protein is an immediate and essential signaling component of interleukin-17receptor[J].J Biol Chem,2006,281(47):35603-35607.
[17]Swaidani S,Bulek K,Kang Z,et al.The critical role of epithelial-derived Act1 in IL-17-and IL-25-mediated pulmonary inflammation[J].J Immunol,2009,182(3):1631-1640.
[18]李艺丹.第一部分:核定位Act1介导组蛋白H3第14位赖氨酸乙酰化和组织因子的转录调控;第二部分:穿心莲内酯(Andro)抗炎与抗血栓机制的研究[D],2009.
[19]Qi C,Wei B,Zhou W,et al.P-selectin-mediated platelet adhesion promotes tumor growth[J].Oncotarget,2015,6(9):6584-6596.
[20]Balch CM,Gershenwald JE,Soong SJ,et al.Final version of2009 AJCC melanoma staging and classification[J].J Clin Oncol,2009,27(36):6199-6206.
[21]Bartkova J,Horejsi Z,Koed K,et al.DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis[J].Nature,2005,434(7035):864-870.
[22]Velichko S,Zhou X,Zhu L,et al.A novel nuclear function for the interleukin-17 signaling adaptor protein Act1[J].PLoSOne,2016,11(10):e0163323.
[23]Huey MG,Minson KA,Earp HS,et al.Targeting the TAMreceptors in leukemia[J].Cancers(Basel),2016,8(11):E101.