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Role of Tgfβ3-Smads-Sp1 Axis in Dcr3-Mediated Immune

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Role of Tgfβ3-Smads-Sp1 Axis in Dcr3-Mediated Immune Zhu et al. Oncogenesis (2019) 8:43 https://doi.org/10.1038/s41389-019-0152-0 Oncogenesis ARTICLE Open Access Role of TGFβ3-Smads-Sp1 axis in DcR3-mediated immune escape of hepatocellular carcinoma Hui-fang Zhu1,2, Yan-ping Liu1, Ding-li Liu3,Yi-danMa1,Zhi-yanHu1,Xiao-yanWang1, Chuan-sha Gu1,2, Yan Zhong1, Ting Long1,He-pingKan4 and Zu-guo Li1,5,6 Abstract Hepatocellular carcinoma (HCC) is a leading cause of tumour-associated mortality worldwide, but no significant improvement in treating HCC has been reported with currently available systemic therapies. Immunotherapy represents a new frontier in tumour therapy. Therefore, the immunobiology of hepatocarcinoma has been under intensive investigation. Decoy receptor 3 (DcR3), a member of the tumour necrosis factor receptor (TNFR) superfamily, is an immune suppressor associated with tumourigenesis and cancer metastasis. However, little is known about the role of DcR3 in the immunobiology of hepatocarcinoma. In this study, we found that overexpression of DcR3 in HCC is mediated by the TGFβ3-Smad-Sp1 signalling pathway, which directly targets DcR3 promoter regions. Moreover, overexpression of DcR3 in HCC tissues is associated with tumour invasion and metastasis and significantly promotes the differentiation and secretion of Th2 and Treg cells while inhibiting the differentiation and secretion of Th1 cells. Conversely, knockdown of DcR3 expression in HCC significantly restored the immunity of CD4+ T cells. Inhibition of DcR3 expression may provide a novel immunotherapeutic approach to restoring immunity in HCC patients. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction regulate the occurrence of HCC in such a micro- Hepatocellular carcinoma (HCC) is one of the most environment has not been elucidated to date. Therefore, common cancers worldwide and has a notably poor the elucidation of the molecular regulation mechanism is prognosis1. The leading factor associated with HCC is likely to create novel avenues for the early identification chronic hepatitis virus infection, which contributes to and therapeutic intervention of HCC. liver injury and concurrent regeneration, giving rise to The immune system functions as a host defensive fibrosis, cirrhosis and, eventually, HCC2. During the mechanism that protects against tumour development. process, the extensive expression of cytokines and che- Patients with tumours exhibit weaker immune surveil- mokines is believed to create a microenvironment that lance capability and a variety of immune dysregulations, + + favours the development of HCC3. However, the including an imbalance of CD4 T cells, CD8 T cells, + mechanism governing how cytokines and chemokines and associated cytokines4,5. Naive CD4 T cells derived from the thymus differentiate into different subtypes at the periphery in response to antigen stimulation. The first + Correspondence: He-ping Kan ([email protected]) or Zu-guo Li classification divided CD4 effector cells into two subsets: ([email protected]) Th1, characterised by the production and release of 1Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515 Guangzhou, interferon gamma (IFN-ɣ), and Th2, characterised by Guangdong, China producing and releasing IL-4. In recent years, it has 2 + Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical become evident that more functional subsets of CD4 University, 601 Jinsui Road, 453003 Xinxiang, Henan, China Full list of author information is available at the end of the article. T cells can be induced by various stimuli in vivo and These authors contributed equally: Hui-fang Zhu, Yan-ping Liu, Ding-li Liu © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Oncogenesis Zhu et al. Oncogenesis (2019) 8:43 Page 2 of 13 in vitro6,7. Another subset is the regulatory T cells (Tregs) determined. The goal of this study was to investigate expressing the transcription factor Foxp3 and T-cell whether DcR3 has the potential to be used as a target for surface molecules CD25/CD127. Treg cells can suppress HCC immunotherapy. the function of other effector T cells and antigen- presenting cells by cell–cell interactions and the release Results of suppressive cytokines, such as TGFβ and IL-10, and Expression of TGFβ3 and DcR3 is upregulated in HCC play a key role in maintaining immunotolerance8,9. The cytokine expression profile analysis between the Although some papers have shown that immunotolerance samples from four patients with HCC and those paired exists in HCC, the specific mechanism governing this adjacent normal hepatic tissues was performed by Ray- phenomenon has not been elucidated to date. Therefore, Bio® human biotin-label-based cytokine antibody arrays, the identification of the key factors mediating tumour- which covered 1000 well-characterised human cytokines. induced immunotolerance in HCC remains to be Interestingly, as shown in Fig. 1a, the expression of DcR3, undertaken. TGFβ3 and TGFβ3 receptor (TGFβRΙ) was upregulated in Transforming growth factor β (TGFβ), a notable tumours compared with normal tissues. These data were molecule in the tumour inflammatory microenvironment, consistent with the hypothesis that the combination of plays critical roles in promoting tumour development, TGFβ3 and TGFβR regulated DcR3 expression in the progression, and immune escape10,11. Three isoforms of HCC microenvironment. TGFβ, i.e., TGFβ1, TGFβ2 and TGFβ3, all function as secreted polypeptides. The isoforms regulate the tran- Upregulation of DcR3 is associated with progression in scriptional expression of tumour cytokines and chemo- HCC kines by binding to TGFβ receptors12,13. Moreover, Real-time PCR and western blotting were performed to accumulating evidence indicates that one efficacious measure the expression of DcR3 in eight cases of primary mechanism by which TGFβ promotes tumour progres- HCC biopsies and their adjacent normal tissues from + sion and metastasis is regulating CD4 T-cell-mediated freshly prepared samples. The results revealed that DcR3 + immunity by inducing the differentiation of CD4 T cells was significantly upregulated in HCC tissues (T) com- into various subpopulations of T cells14. In the HCC pared with their paired adjacent normal hepatic tissues microenvironment, we found that the expression of (N) (Fig. 1b, c). TGFβ3 was higher than that in normal liver tissues. In addition, IHC was used to determine the expression However, the effect of TGFβ3 to HCC and the molecular level of DcR3 in 91 cases of paraffin-embedded HCC basis for such effect has not been fully elucidated. sections. As shown in Fig. 1d, DcR3 protein was located in Decoy receptor 3 (DcR3), a member of the tumour the cytoplasm HCC cells, and the expression of DcR3 necrosis factor receptor (TNFR) superfamily, is a soluble increased markedly in 85.7% (78/91) of HCC tissues secretory protein lacking a transmembrane sequence15. compared with that in adjacent non-tumour tissue (Sup- DcR3 has three ligands: Fas ligand (FasL), TNF-like porting Table S1). The correlation between DcR3 molecule 1 A (TL1A), and lymphotoxin-related inducible expression and the clinicopathological features of HCC ligand, which competes with herpes simplex virus glyco- was analysed by chi-square test. As summarised in Sup- protein D for herpesvirus entry mediator on T cells porting Table S2, correlation analysis showed that DcR3 – (LIGHT)16 18. DcR3 is barely detectable in normal tissue expression was associated with liver cirrhosis (P < 0.001), and serum of healthy subjects, whereas its expression is HbsAg infection (P < 0.001), tumour differentiation increased in various tumours, such as breast cancer19, (P = 0.033), metastasis (P = 0.013), and portal vein gastric cancer20, glioma21, pancreatic carcinoma22, and tumour thrombus (PVTT) (P = 0.012). renal cell carcinoma23. There is strong evidence indicating As DcR3 is a soluble secretory protein lacking a trans- that overexpression of DcR3 causes it to function as a membrane sequence, DcR3 serum levels were detected by decoy receptor for FasL, TL1A, and LIGHT and inhibits enzyme-linked immune sorbent assay (ELISA). As shown these ligands, mediates apoptosis, angiogenesis, pro- in Fig. 1e, the DcR3 serum level in HCC patients liferation, differentiation and lymphokine secretion of (Tumour) was higher than that in normal controls lymphocyte, which makes DcR3 a potential therapeutic (P < 0.001). Taken together, these results indicate that target in cancers21,22,24,25. In a previous study, we increased DcR3 expression is clinically relevant to the demonstrated that DcR3 was one of the key molecules occurrence of HCC. that regulated colorectal cancer (CRC) tumourigenesis and
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