Skip to main content
Top
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Special role of Foxp3 for the specifically altered microRNAs in Regulatory T cells of HCC patients

Authors: Long Chen, Huiying Ma, Heng Hu, Lingling Gao, Xuan Wang, Jiaqi Ma, Qiang Gao, Binbin Liu, Guomin Zhou, Chunmin Liang

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

Regulatory T cells (Tregs) exhibit functional abnormalities in the context of hepatocellular carcinoma (HCC). The microRNAs (miRNAs) are identified as the key modulators in Tregs. This study was to explore whether the expression profiles of miRNAs of Tregs were different in HCC-activated Tregs and whether Foxp3 had special effects on them.

Methods

We isolated HCC-activated Tregs from mice bearing HCC and compared the expression profiles of miRNAs between HCC-activated Tregs and control Tregs by microarray. RNA interference against Foxp3 was also performed through transfection of synthetic siRNAs to Tregs for analyzing the effect of Foxp3 on the expression of miRNAs. Tregs isolated from HCC patients (n = 12) and healthy controls (n = 7) were used for validation of the differentially expressed miRNAs. Finally, bioinformatic analysis was applied to infer their possible roles.

Results

We found nine specifically altered miRNAs in HCC-activated Tregs from the murine model. After transfection with siRNAs against Foxp3, control Tregs showed obvious reduction of Foxp3 and five miRNAs were significantly changed; HCC-activated Tregs exhibited a slight reduction of Foxp3 with three miRNAs significantly changed. Tregs from HCC patients and healthy controls finally confirmed the up-regulation of four miRNAs (hsa-miR-182-5p, hsa-miR-214-3p, hsa-miR-129-5p and hsa-miR-30b-5p). Following bioinformatic analysis suggested these altered miRNAs would target eight important signaling pathways that could affect the functions of Tregs.

Conclusions

Our studies provided the first evidence that Tregs in HCC had the specifically altered expression of miRNAs, which was affected by Foxp3. These results are useful both in finding new biomarkers and in further exploring the functions of Tregs in HCC patients.
Appendix
Available only for authorised users
Literature
2.
go back to reference Zhou J, Ding T, Pan W, Zhu LY, Li L, Zheng L: Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer. 2009, 125 (7): 1640-1648.CrossRefPubMed Zhou J, Ding T, Pan W, Zhu LY, Li L, Zheng L: Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer. 2009, 125 (7): 1640-1648.CrossRefPubMed
3.
4.
go back to reference Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C, Yao J, Jin L, Wang H, Yang Y, Fu YX, Wang FS: Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007, 132 (7): 2328-2339.CrossRefPubMed Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C, Yao J, Jin L, Wang H, Yang Y, Fu YX, Wang FS: Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007, 132 (7): 2328-2339.CrossRefPubMed
5.
go back to reference Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007, 25 (18): 2586-2593.CrossRefPubMed Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007, 25 (18): 2586-2593.CrossRefPubMed
6.
go back to reference Shen X, Li N, Li H, Zhang T, Wang F, Li Q: Increased prevalence of regulatory T cells in the tumor microenvironment and its correlation with TNM stage of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2010, 136 (11): 1745-1754.CrossRefPubMed Shen X, Li N, Li H, Zhang T, Wang F, Li Q: Increased prevalence of regulatory T cells in the tumor microenvironment and its correlation with TNM stage of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2010, 136 (11): 1745-1754.CrossRefPubMed
7.
go back to reference Takata Y, Nakamoto Y, Nakada A, Terashima T, Arihara F, Kitahara M, Kakinoki K, Arai K, Yamashita T, Sakai Y, Mizukoshi E, Kaneko S: Frequency of CD45RO + subset in CD4 + CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma. Cancer Lett. 2011, 307 (2): 165-173.CrossRefPubMed Takata Y, Nakamoto Y, Nakada A, Terashima T, Arihara F, Kitahara M, Kakinoki K, Arai K, Yamashita T, Sakai Y, Mizukoshi E, Kaneko S: Frequency of CD45RO + subset in CD4 + CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma. Cancer Lett. 2011, 307 (2): 165-173.CrossRefPubMed
9.
go back to reference Chen KJ, Lin SZ, Zhou L, Xie HY, Zhou WH, Taki-Eldin A, Zheng SS: Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE. 2011, 6 (9): e24671-CrossRefPubMedPubMedCentral Chen KJ, Lin SZ, Zhou L, Xie HY, Zhou WH, Taki-Eldin A, Zheng SS: Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE. 2011, 6 (9): e24671-CrossRefPubMedPubMedCentral
10.
go back to reference Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, Peppelenbosch MP, Kwekkeboom J, Verheij J, Janssen HL, Sprengers D: Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology. 2013, 57 (1): 183-194.CrossRefPubMed Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, Peppelenbosch MP, Kwekkeboom J, Verheij J, Janssen HL, Sprengers D: Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology. 2013, 57 (1): 183-194.CrossRefPubMed
11.
go back to reference Cao M, Cabrera R, Xu Y, Firpi R, Zhu H, Liu C, Nelson DR: Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+)CD25(+) regulatory T cells. Lab Invest. 2007, 87 (6): 582-590.PubMed Cao M, Cabrera R, Xu Y, Firpi R, Zhu H, Liu C, Nelson DR: Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+)CD25(+) regulatory T cells. Lab Invest. 2007, 87 (6): 582-590.PubMed
12.
go back to reference Cabrera R, Ararat M, Eksioglu EA, Cao M, Xu Y, Wasserfall C, Atkinson MA, Liu C, Nelson DR: Influence of serum and soluble CD25 (sCD25) on regulatory and effector T-cell function in hepatocellular carcinoma. Scand J Immunol. 2010, 72 (4): 293-301.CrossRefPubMedPubMedCentral Cabrera R, Ararat M, Eksioglu EA, Cao M, Xu Y, Wasserfall C, Atkinson MA, Liu C, Nelson DR: Influence of serum and soluble CD25 (sCD25) on regulatory and effector T-cell function in hepatocellular carcinoma. Scand J Immunol. 2010, 72 (4): 293-301.CrossRefPubMedPubMedCentral
13.
go back to reference Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell. 2008, 133 (5): 775-787.CrossRefPubMed Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell. 2008, 133 (5): 775-787.CrossRefPubMed
14.
go back to reference Gao Y, Lin F, Su J, Gao Z, Li Y, Yang J, Deng Z, Liu B, Tsun A, Li B: Molecular mechanisms underlying the regulation and functional plasticity of FOXP3(+) regulatory T cells. Genes Immun. 2012, 13 (1): 1-13.CrossRefPubMed Gao Y, Lin F, Su J, Gao Z, Li Y, Yang J, Deng Z, Liu B, Tsun A, Li B: Molecular mechanisms underlying the regulation and functional plasticity of FOXP3(+) regulatory T cells. Genes Immun. 2012, 13 (1): 1-13.CrossRefPubMed
15.
go back to reference Xiao C, Rajewsky K: MicroRNA control in the immune system: basic principles. Cell. 2009, 136 (1): 26-36.CrossRefPubMed Xiao C, Rajewsky K: MicroRNA control in the immune system: basic principles. Cell. 2009, 136 (1): 26-36.CrossRefPubMed
16.
go back to reference Liston A, Lu LF, O’Carroll D, Tarakhovsky A, Rudensky AY: Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med. 2008, 205 (9): 1993-2004.CrossRefPubMedPubMedCentral Liston A, Lu LF, O’Carroll D, Tarakhovsky A, Rudensky AY: Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med. 2008, 205 (9): 1993-2004.CrossRefPubMedPubMedCentral
17.
go back to reference Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothe F, Simion A, Akl H, Mourtada M, El Rifai M, Burny A, Romero P, Martiat P, Badran B: Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol. 2009, 39 (6): 1608-1618.CrossRefPubMed Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothe F, Simion A, Akl H, Mourtada M, El Rifai M, Burny A, Romero P, Martiat P, Badran B: Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol. 2009, 39 (6): 1608-1618.CrossRefPubMed
18.
go back to reference Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K, Rudensky AY: Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity. 2009, 30 (1): 80-91.CrossRefPubMedPubMedCentral Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K, Rudensky AY: Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity. 2009, 30 (1): 80-91.CrossRefPubMedPubMedCentral
19.
go back to reference Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E: Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol. 2009, 182 (5): 2578-2582.CrossRefPubMed Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E: Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol. 2009, 182 (5): 2578-2582.CrossRefPubMed
20.
go back to reference Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY: Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010, 142 (6): 914-929.CrossRefPubMedPubMedCentral Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY: Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010, 142 (6): 914-929.CrossRefPubMedPubMedCentral
21.
go back to reference Lewis BP, Burge CB, Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005, 120 (1): 15-20.CrossRefPubMed Lewis BP, Burge CB, Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005, 120 (1): 15-20.CrossRefPubMed
23.
go back to reference da Huang W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009, 4 (1): 44-57.CrossRefPubMed da Huang W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009, 4 (1): 44-57.CrossRefPubMed
24.
go back to reference Jindra PT, Bagley J, Godwin JG, Iacomini J: Costimulation-dependent expression of microRNA-214 increases the ability of T cells to proliferate by targeting Pten. J Immunol. 2010, 185 (2): 990-997.CrossRefPubMedPubMedCentral Jindra PT, Bagley J, Godwin JG, Iacomini J: Costimulation-dependent expression of microRNA-214 increases the ability of T cells to proliferate by targeting Pten. J Immunol. 2010, 185 (2): 990-997.CrossRefPubMedPubMedCentral
25.
go back to reference Divekar AA, Dubey S, Gangalum PR, Singh RR: Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu. J Immunol. 2011, 186 (2): 924-930.CrossRefPubMed Divekar AA, Dubey S, Gangalum PR, Singh RR: Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu. J Immunol. 2011, 186 (2): 924-930.CrossRefPubMed
26.
go back to reference Li J, Wan Y, Guo Q, Zou L, Zhang J, Fang Y, Fu X, Liu H, Lu L, Wu Y: Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res Ther. 2010, 12 (3): R81-CrossRefPubMedPubMedCentral Li J, Wan Y, Guo Q, Zou L, Zhang J, Fang Y, Fu X, Liu H, Lu L, Wu Y: Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res Ther. 2010, 12 (3): R81-CrossRefPubMedPubMedCentral
27.
go back to reference De Santis G, Ferracin M, Biondani A, Caniatti L, Rosaria Tola M, Castellazzi M, Zagatti B, Battistini L, Borsellino G, Fainardi E, Gavioli R, Negrini M, Furlan R, Granieri E: Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J Neuroimmunol. 2010, 226 (1–2): 165-171.CrossRefPubMed De Santis G, Ferracin M, Biondani A, Caniatti L, Rosaria Tola M, Castellazzi M, Zagatti B, Battistini L, Borsellino G, Fainardi E, Gavioli R, Negrini M, Furlan R, Granieri E: Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J Neuroimmunol. 2010, 226 (1–2): 165-171.CrossRefPubMed
28.
go back to reference Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, Heinz GA, Kremmer E, Heissmeyer V, McManus MT, Erle DJ, Rao A, Ansel KM: T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire. J Exp Med. 2013, 210 (2): 417-432.CrossRefPubMedPubMedCentral Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, Heinz GA, Kremmer E, Heissmeyer V, McManus MT, Erle DJ, Rao A, Ansel KM: T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire. J Exp Med. 2013, 210 (2): 417-432.CrossRefPubMedPubMedCentral
29.
go back to reference Ohkura N, Sakaguchi S: Treg cells acquire new directions, cytokines navigate. Immunity. 2012, 37 (3): 443-444.CrossRefPubMed Ohkura N, Sakaguchi S: Treg cells acquire new directions, cytokines navigate. Immunity. 2012, 37 (3): 443-444.CrossRefPubMed
30.
go back to reference Zheng Y, Chaudhry A, Kas A, de Roos P, Kim JM, Chu TT, Corcoran L, Treuting P, Klein U, Rudensky AY: Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009, 458 (7236): 351-356.CrossRefPubMedPubMedCentral Zheng Y, Chaudhry A, Kas A, de Roos P, Kim JM, Chu TT, Corcoran L, Treuting P, Klein U, Rudensky AY: Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009, 458 (7236): 351-356.CrossRefPubMedPubMedCentral
31.
go back to reference Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, Pritchard GH, Silver JS, Bouladoux N, Stumhofer JS, Harris TH, Grainger J, Wojno ED, Wagage S, Roos DS, Scott P, Turka LA, Cherry S, Reiner SL, Cua D, Belkaid Y, Elloso MM, Hunter CA: The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity. 2012, 37 (3): 511-523.CrossRefPubMedPubMedCentral Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, Pritchard GH, Silver JS, Bouladoux N, Stumhofer JS, Harris TH, Grainger J, Wojno ED, Wagage S, Roos DS, Scott P, Turka LA, Cherry S, Reiner SL, Cua D, Belkaid Y, Elloso MM, Hunter CA: The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity. 2012, 37 (3): 511-523.CrossRefPubMedPubMedCentral
32.
go back to reference Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, Rudensky AY: CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009, 326 (5955): 986-991.CrossRefPubMedPubMedCentral Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, Rudensky AY: CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009, 326 (5955): 986-991.CrossRefPubMedPubMedCentral
33.
go back to reference Sun L, Wu J, Yi S: Foxp3 is critical for human natural CD4 + CD25+ regulatory T cells to suppress alloimmune response. Transpl Immunol. 2012, 26 (2–3): 71-80.CrossRefPubMed Sun L, Wu J, Yi S: Foxp3 is critical for human natural CD4 + CD25+ regulatory T cells to suppress alloimmune response. Transpl Immunol. 2012, 26 (2–3): 71-80.CrossRefPubMed
34.
go back to reference van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YYJ, Beekman JM, van Beekum O, Brenkman AB, Hijnen DJ, Mutis T, Kalkhoven E, Prakken BJ, Coffer PJ: Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood. 2009, 115: 965-974.CrossRefPubMed van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YYJ, Beekman JM, van Beekum O, Brenkman AB, Hijnen DJ, Mutis T, Kalkhoven E, Prakken BJ, Coffer PJ: Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood. 2009, 115: 965-974.CrossRefPubMed
35.
go back to reference Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, Liu X, Xiao L, Chen X, Wan B, Chin YE, Zhang JZ: Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med. 2013, 19 (3): 322-328.CrossRefPubMed Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, Liu X, Xiao L, Chen X, Wan B, Chin YE, Zhang JZ: Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med. 2013, 19 (3): 322-328.CrossRefPubMed
36.
go back to reference Korn T, Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G, Vollmar P, Stritesky GL, Kaplan MH, Waisman A, Kuchroo VK, Oukka M: IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A. 2008, 105 (47): 18460-18465.CrossRefPubMedPubMedCentral Korn T, Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G, Vollmar P, Stritesky GL, Kaplan MH, Waisman A, Kuchroo VK, Oukka M: IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A. 2008, 105 (47): 18460-18465.CrossRefPubMedPubMedCentral
37.
go back to reference Yadav M, Huang MC, Goetzl EJ: VPAC1 (vasoactive intestinal peptide (VIP) receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis. Cell Immunol. 2011, 267 (2): 124-132.CrossRefPubMed Yadav M, Huang MC, Goetzl EJ: VPAC1 (vasoactive intestinal peptide (VIP) receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis. Cell Immunol. 2011, 267 (2): 124-132.CrossRefPubMed
38.
go back to reference Gomez-Rodriguez J, Sahu N, Handon R, Davidson TS, Anderson SM, Kirby MR, August A, Schwartzberg PL: Differential expression of interleukin-17A and -17 F is coupled to T cell receptor signaling via inducible T cell kinase. Immunity. 2009, 31 (4): 587-597.CrossRefPubMedPubMedCentral Gomez-Rodriguez J, Sahu N, Handon R, Davidson TS, Anderson SM, Kirby MR, August A, Schwartzberg PL: Differential expression of interleukin-17A and -17 F is coupled to T cell receptor signaling via inducible T cell kinase. Immunity. 2009, 31 (4): 587-597.CrossRefPubMedPubMedCentral
39.
go back to reference Yang XH, Yamagiwa S, Ichida T, Matsuda Y, Sugahara S, Watanabe H, Sato Y, Abo T, Horwitz DA, Aoyagi Y: Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol. 2006, 45 (2): 254-262.CrossRefPubMed Yang XH, Yamagiwa S, Ichida T, Matsuda Y, Sugahara S, Watanabe H, Sato Y, Abo T, Horwitz DA, Aoyagi Y: Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol. 2006, 45 (2): 254-262.CrossRefPubMed
40.
go back to reference Zabala M, Lasarte JJ, Perret C, Sola J, Berraondo P, Alfaro M, Larrea E, Prieto J, Kramer MG: Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer. J Hepatol. 2007, 47 (6): 807-815.CrossRefPubMed Zabala M, Lasarte JJ, Perret C, Sola J, Berraondo P, Alfaro M, Larrea E, Prieto J, Kramer MG: Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer. J Hepatol. 2007, 47 (6): 807-815.CrossRefPubMed
41.
go back to reference Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, Deng Y, Zhao J, Jiang S, Yuan Y, Wang HY, Cheng SQ, Xie D, Wang XF: TGF-beta-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma. Cancer Cell. 2012, 22 (3): 291-303.CrossRefPubMedPubMedCentral Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, Deng Y, Zhao J, Jiang S, Yuan Y, Wang HY, Cheng SQ, Xie D, Wang XF: TGF-beta-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma. Cancer Cell. 2012, 22 (3): 291-303.CrossRefPubMedPubMedCentral
42.
go back to reference Ueha S, Yoneyama H, Hontsu S, Kurachi M, Kitabatake M, Abe J, Yoshie O, Shibayama S, Sugiyama T, Matsushima K: CCR7 mediates the migration of Foxp3+ regulatory T cells to the paracortical areas of peripheral lymph nodes through high endothelial venules. J Leukoc Biol. 2007, 82 (5): 1230-1238.CrossRefPubMed Ueha S, Yoneyama H, Hontsu S, Kurachi M, Kitabatake M, Abe J, Yoshie O, Shibayama S, Sugiyama T, Matsushima K: CCR7 mediates the migration of Foxp3+ regulatory T cells to the paracortical areas of peripheral lymph nodes through high endothelial venules. J Leukoc Biol. 2007, 82 (5): 1230-1238.CrossRefPubMed
43.
go back to reference Eikawa S, Ohue Y, Kitaoka K, Aji T, Uenaka A, Oka M, Nakayama E: Enrichment of Foxp3+ CD4 regulatory T cells in migrated T cells to IL-6- and IL-8-expressing tumors through predominant induction of CXCR1 by IL-6. J Immunol. 2010, 185 (11): 6734-6740.CrossRefPubMed Eikawa S, Ohue Y, Kitaoka K, Aji T, Uenaka A, Oka M, Nakayama E: Enrichment of Foxp3+ CD4 regulatory T cells in migrated T cells to IL-6- and IL-8-expressing tumors through predominant induction of CXCR1 by IL-6. J Immunol. 2010, 185 (11): 6734-6740.CrossRefPubMed
44.
go back to reference Zhang N, Schroppel B, Lal G, Jakubzick C, Mao X, Chen D, Yin N, Jessberger R, Ochando JC, Ding Y, Bromberg JS: Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity. 2009, 30 (3): 458-469.CrossRefPubMedPubMedCentral Zhang N, Schroppel B, Lal G, Jakubzick C, Mao X, Chen D, Yin N, Jessberger R, Ochando JC, Ding Y, Bromberg JS: Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity. 2009, 30 (3): 458-469.CrossRefPubMedPubMedCentral
45.
go back to reference Chauhan S, Saban D, Lee H, Dana R: Levels of Foxp3 in regulatory T cells reflect their functional status in transplantation. J Immunol. 2009, 182 (1): 148-153.CrossRefPubMedPubMedCentral Chauhan S, Saban D, Lee H, Dana R: Levels of Foxp3 in regulatory T cells reflect their functional status in transplantation. J Immunol. 2009, 182 (1): 148-153.CrossRefPubMedPubMedCentral
46.
go back to reference Joffre O, Santolaria T, Calise D, Saati TA, Hudrisier D, Romagnoli P, van Meerwijk JPM: Prevention of acute and chronic allograft rejection with CD4 + CD25 + Foxp3+ regulatory T lymphocytes. Nat Med. 2007, 14 (1): 88-92.CrossRefPubMedPubMedCentral Joffre O, Santolaria T, Calise D, Saati TA, Hudrisier D, Romagnoli P, van Meerwijk JPM: Prevention of acute and chronic allograft rejection with CD4 + CD25 + Foxp3+ regulatory T lymphocytes. Nat Med. 2007, 14 (1): 88-92.CrossRefPubMedPubMedCentral
47.
go back to reference Fan Z, Spencer JA, Lu Y, Pitsillides CM, Singh G, Kim P, Yun SH, Toxavidis V, Strom TB, Lin CP, Koulmanda M: In vivo tracking of ‘color-coded’ effector, natural and induced regulatory T cells in the allograft response. Nat Med. 2010, 16 (6): 718-722.CrossRefPubMedPubMedCentral Fan Z, Spencer JA, Lu Y, Pitsillides CM, Singh G, Kim P, Yun SH, Toxavidis V, Strom TB, Lin CP, Koulmanda M: In vivo tracking of ‘color-coded’ effector, natural and induced regulatory T cells in the allograft response. Nat Med. 2010, 16 (6): 718-722.CrossRefPubMedPubMedCentral
48.
go back to reference Cong Y, Feng T, Fujihashi K, Schoeb TR, Elson CO: A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc Natl Acad Sci U S A. 2009, 106 (46): 19256-19261.CrossRefPubMedPubMedCentral Cong Y, Feng T, Fujihashi K, Schoeb TR, Elson CO: A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc Natl Acad Sci U S A. 2009, 106 (46): 19256-19261.CrossRefPubMedPubMedCentral
49.
go back to reference Borsutzky S, Cazac BB, Roes J, Guzman CA: TGF-beta receptor signaling is critical for mucosal IgA responses. J Immunol. 2004, 173 (5): 3305-3309.CrossRefPubMed Borsutzky S, Cazac BB, Roes J, Guzman CA: TGF-beta receptor signaling is critical for mucosal IgA responses. J Immunol. 2004, 173 (5): 3305-3309.CrossRefPubMed
51.
go back to reference Matharu KS, Mizoguchi E, Cotoner CA, Nguyen DD, Mingle B, Iweala OI, McBee ME, Stefka AT, Prioult G, Haigis KM, Bhan AK, Snapper SB, Murakami H, Schauer DB, Reinecker HC, Mizoguchi A, Nagler CR: Toll-like receptor 4-mediated regulation of spontaneous helicobacter-dependent colitis in IL-10–deficient mice. Gastroenterology. 2009, 137 (4): 1380-1390. e1383CrossRefPubMedPubMedCentral Matharu KS, Mizoguchi E, Cotoner CA, Nguyen DD, Mingle B, Iweala OI, McBee ME, Stefka AT, Prioult G, Haigis KM, Bhan AK, Snapper SB, Murakami H, Schauer DB, Reinecker HC, Mizoguchi A, Nagler CR: Toll-like receptor 4-mediated regulation of spontaneous helicobacter-dependent colitis in IL-10–deficient mice. Gastroenterology. 2009, 137 (4): 1380-1390. e1383CrossRefPubMedPubMedCentral
52.
go back to reference Forward NA, Furlong SJ, Yang Y, Lin TJ, Hoskin DW: Signaling through TLR7 enhances the immunosuppressive activity of murine CD4 + CD25+ T regulatory cells. J Leukoc Biol. 2009, 87 (1): 117-125.CrossRefPubMed Forward NA, Furlong SJ, Yang Y, Lin TJ, Hoskin DW: Signaling through TLR7 enhances the immunosuppressive activity of murine CD4 + CD25+ T regulatory cells. J Leukoc Biol. 2009, 87 (1): 117-125.CrossRefPubMed
53.
go back to reference Nyirenda MH, Sanvito L, Darlington PJ, O’Brien K, Zhang GX, Constantinescu CS, Bar-Or A, Gran B: TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol. 2011, 187 (5): 2278-2290.CrossRefPubMed Nyirenda MH, Sanvito L, Darlington PJ, O’Brien K, Zhang GX, Constantinescu CS, Bar-Or A, Gran B: TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol. 2011, 187 (5): 2278-2290.CrossRefPubMed
54.
go back to reference Zhang Y, Luo F, Cai Y, Liu N, Wang L, Xu D, Chu Y: TLR1/TLR2 agonist induces tumor regression by reciprocal modulation of effector and regulatory T cells. J Immunol. 2011, 186 (4): 1963-1969.CrossRefPubMed Zhang Y, Luo F, Cai Y, Liu N, Wang L, Xu D, Chu Y: TLR1/TLR2 agonist induces tumor regression by reciprocal modulation of effector and regulatory T cells. J Immunol. 2011, 186 (4): 1963-1969.CrossRefPubMed
Metadata
Title
Special role of Foxp3 for the specifically altered microRNAs in Regulatory T cells of HCC patients
Authors
Long Chen
Huiying Ma
Heng Hu
Lingling Gao
Xuan Wang
Jiaqi Ma
Qiang Gao
Binbin Liu
Guomin Zhou
Chunmin Liang
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-489

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine