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Article: Soluble fibrinogen-like protein 2 promotes the growth of hepatocellular carcinoma via attenuating dendritic cell-mediated cytotoxic T cell activity

TitleSoluble fibrinogen-like protein 2 promotes the growth of hepatocellular carcinoma via attenuating dendritic cell-mediated cytotoxic T cell activity
Authors
KeywordsSoluble fibrinogen-like protein 2
Hepatocellular carcinoma
Tumor microenvironment
Dendritic
Issue Date2019
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.jeccr.com/home
Citation
Journal of Experimental and Clinical Cancer Research, 2019, v. 38, p. article no. 351 How to Cite?
AbstractBackground: Soluble fibrinogen-like protein 2 (sFGL2), a secretory protein expressed by regulatory T cells (Tregs) with immunosuppressive activity, is highly expressed in both the peripheral blood and tumor tissue of patients with hepatocellular carcinoma (HCC); however, sFGL2 function in HCC remains largely unknown. Here, we elucidated the potential role of sFGL2 in HCC progression. Methods: T cells, dendritic cells (DCs), and related cytokines in the tumor microenvironment were comparatively analyzed in BALB/c and C57BL/6 mice bearing transplanted hepatomas harboring Fgl2-knockout or receiving sFGL2-antibody treatment. Additionally, the effects of sFGL2 on DCs and T cells were evaluated in vivo and ex vivo. Results: The growth of both subcutaneously and orthotopically transplanted hepatomas was inhibited in Fgl2-knockout mice and those treated with the sFGL2 antibody, respectively, as compared with controls. Moreover, sFGL2 depletion enhanced the proportion and cytotoxicity of cytotoxic T cells, promoted DC maturation, and improved DC activity to proliferate T cells in the tumor microenvironment. Furthermore, we detected lower levels of interleukin (IL)-35 in both types of transplanted hepatomas and higher level of IL-6 in orthotopically transplanted hepatomas following sFGL2 depletion. Mechanistically, we found that sFGL2 impaired bone-marrow-derived DC (BMDCs) function by inhibiting phosphorylation of Akt, nuclear factor-kappaB, cAMP response element binding protein, and p38 and downregulating the expression of major histocompatibility complex II, CD40, CD80, CD86, and CD83 on BMDCs in vitro. Conclusions: Our data suggest that sFGL2 promotes hepatoma growth by attenuating DC activity and subsequent CD8+ T cell cytotoxicity, suggesting sFGL2 as a novel potential therapeutic target for HCC treatment.
Persistent Identifierhttp://hdl.handle.net/10722/275107
ISSN
2018 Impact Factor: 5.646
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYang, M-
dc.contributor.authorZhang, Z-
dc.contributor.authorChen, J-
dc.contributor.authorXu, M-
dc.contributor.authorHuang, J-
dc.contributor.authorWang, M-
dc.contributor.authorLi, W-
dc.contributor.authorWan, X-
dc.contributor.authorYuen, MF-
dc.contributor.authorLuo, X-
dc.contributor.authorXi, D-
dc.contributor.authorNing, Q-
dc.date.accessioned2019-09-10T02:35:36Z-
dc.date.available2019-09-10T02:35:36Z-
dc.date.issued2019-
dc.identifier.citationJournal of Experimental and Clinical Cancer Research, 2019, v. 38, p. article no. 351-
dc.identifier.issn1756-9966-
dc.identifier.urihttp://hdl.handle.net/10722/275107-
dc.description.abstractBackground: Soluble fibrinogen-like protein 2 (sFGL2), a secretory protein expressed by regulatory T cells (Tregs) with immunosuppressive activity, is highly expressed in both the peripheral blood and tumor tissue of patients with hepatocellular carcinoma (HCC); however, sFGL2 function in HCC remains largely unknown. Here, we elucidated the potential role of sFGL2 in HCC progression. Methods: T cells, dendritic cells (DCs), and related cytokines in the tumor microenvironment were comparatively analyzed in BALB/c and C57BL/6 mice bearing transplanted hepatomas harboring Fgl2-knockout or receiving sFGL2-antibody treatment. Additionally, the effects of sFGL2 on DCs and T cells were evaluated in vivo and ex vivo. Results: The growth of both subcutaneously and orthotopically transplanted hepatomas was inhibited in Fgl2-knockout mice and those treated with the sFGL2 antibody, respectively, as compared with controls. Moreover, sFGL2 depletion enhanced the proportion and cytotoxicity of cytotoxic T cells, promoted DC maturation, and improved DC activity to proliferate T cells in the tumor microenvironment. Furthermore, we detected lower levels of interleukin (IL)-35 in both types of transplanted hepatomas and higher level of IL-6 in orthotopically transplanted hepatomas following sFGL2 depletion. Mechanistically, we found that sFGL2 impaired bone-marrow-derived DC (BMDCs) function by inhibiting phosphorylation of Akt, nuclear factor-kappaB, cAMP response element binding protein, and p38 and downregulating the expression of major histocompatibility complex II, CD40, CD80, CD86, and CD83 on BMDCs in vitro. Conclusions: Our data suggest that sFGL2 promotes hepatoma growth by attenuating DC activity and subsequent CD8+ T cell cytotoxicity, suggesting sFGL2 as a novel potential therapeutic target for HCC treatment.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.jeccr.com/home-
dc.relation.ispartofJournal of Experimental and Clinical Cancer Research-
dc.rightsJournal of Experimental and Clinical Cancer Research. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectSoluble fibrinogen-like protein 2-
dc.subjectHepatocellular carcinoma-
dc.subjectTumor microenvironment-
dc.subjectDendritic-
dc.titleSoluble fibrinogen-like protein 2 promotes the growth of hepatocellular carcinoma via attenuating dendritic cell-mediated cytotoxic T cell activity-
dc.typeArticle-
dc.identifier.emailYuen, MF: mfyuen@hku.hk-
dc.identifier.authorityYuen, MF=rp00479-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s13046-019-1326-5-
dc.identifier.pmid31409352-
dc.identifier.pmcidPMC6693134-
dc.identifier.scopuseid_2-s2.0-85070747151-
dc.identifier.hkuros304368-
dc.identifier.volume38-
dc.identifier.spagearticle no. 351-
dc.identifier.epagearticle no. 351-
dc.identifier.isiWOS:000480773000002-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl1756-9966-

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