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Zhu HF, Liu YP, Liu DL, Ma YD, Hu ZY, Wang XY, Gu CS, Zhong Y, Long T, Kan HP, Li ZG. Role of TGFβ3-Smads-Sp1 axis in DcR3-mediated immune escape of hepatocellular carcinoma. Oncogenesis 2019; 8:43. [PMID: 31409774 PMCID: PMC6692328 DOI: 10.1038/s41389-019-0152-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/04/2019] [Accepted: 06/21/2019] [Indexed: 12/12/2022] Open
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.
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Affiliation(s)
- Hui-Fang Zhu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, 453003, Xinxiang, Henan, China
| | - Yan-Ping Liu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China
| | - Ding-Li Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1023 South Shatai Road, Baiyun District, 510515, Guangzhou, Guangdong, China
| | - Yi-Dan Ma
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China
| | - Zhi-Yan Hu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China
| | - Xiao-Yan Wang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China
| | - Chuan-Sha Gu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, 453003, Xinxiang, Henan, China
| | - Yan Zhong
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China
| | - Ting Long
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China
| | - He-Ping Kan
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China.
| | - Zu-Guo Li
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1023 South Shatai Rd, Baiyun District, 510515, Guangzhou, Guangdong, China. .,Department of Pathology, Shenzhen Hospital, Southern Medical University, 1333 Xin-hu Road, Bao'an District, 518100, Shenzhen, Guangdong, China. .,Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center, Shenzhen Hospital, Southern Medical University, 1333 Xin-hu Road, Bao'an District, 518100, Shenzhen, Guangdong, China.
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Abstract
Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor (TNFR) superfamily member 6b (TNFRSF6B), is a soluble decoy receptor which can neutralize the biological functions of three members of tumor necrosis factor superfamily (TNFSF): Fas ligand (FasL), LIGHT, and TL1A. In addition to ‘decoy’ function, recombinant DcR3.Fc is able to modulate the activation and differentiation of dendritic cells (DCs) and macrophages via ‘non-decoy’ action. DcR3-treated DCs skew T cell differentiation into Th2 phenotype, while DcR3-treated macrophages behave M2 phenotype. DcR3 is upregulated in various cancer cells and several inflammatory tissues, and is regarded as a potential biomarker to predict inflammatory disease progression and cancer metastasis. However, whether DcR3 is a pathogenic factor or a suppressor to attenuate inflammatory reactions, has not been discussed comprehensively yet. Because mouse genome does not have DcR3, it is not feasible to investigate its physiological functions by gene-knockout approach. However, DcR3-mediated effects in vitro are determined via overexpressing DcR3 or addition of recombinant DcR3.Fc fusion protein. Moreover, CD68-driven DcR3 transgenic mice are used to investigate DcR3-mediated systemic effects in vivo. Upregulation of DcR3 during inflammatory reactions exerts negative-feedback to suppress inflammation, while tumor cells hijack DcR3 to prevent apoptosis and promote tumor growth and invasion. Thus, ‘switch-on’ of DcR3 expression may be feasible for the treatment of inflammatory diseases and enhance tissue repairing, while ‘switch-off’ of DcR3 expression can enhance tumor apoptosis and suppress tumor growth in vivo.
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Affiliation(s)
- Shie-Liang Hsieh
- Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 115, Taiwan. .,Institute of Clinical Medicine & Immunology Research Center, National Yang-Ming University, Taipei, Taiwan. .,Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan. .,Institute of Immunology, College of Medicine, National Taiwan University Taipei, Taipei, Taiwan. .,Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, No. 1 Section 1, Jen Ai Road, Taipei, 10001, Taiwan.
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The expression of death decoy receptor 3 was increased in the patients with primary Sjögren's syndrome. Clin Rheumatol 2015; 34:879-85. [PMID: 25564309 DOI: 10.1007/s10067-014-2853-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 11/15/2014] [Accepted: 12/15/2014] [Indexed: 10/24/2022]
Abstract
Previous studies suggested a pathological role for the death decoy receptor 3 (DcR3) in systemic lupus erythematosus (SLE) and rheumatic arthritis (RA). Herein, the expression of DcR3 in primary Sjögren's syndrome (pSS) and the relationship with clinical characteristics were investigated. The serum DcR3 levels of pSS patients and healthy controls were measured by ELISA. Pearson's correlation analysis was used to evaluate the relationship between the DcR3 levels with the clinical characterstics of pSS patients. Additionally, the DcR3 expression in salivary glands of pSS patients was investigated by the immunohistochemistry method. The serum DcR3 expression in pSS patients was significantly higher than healthy controls (p < 0.001), especially in new onset pSS patients (p = 0.036). Moreover, Pearson's correlation analysis show that DcR3 levels were positively correlated with age (p = 0.013), platelet (PLT) (p = 0.002), hemoglobin (Hb) (p = 0.004), Sjögren's syndrome disease damage activity index (SSDAI) score (p = 0.005), Sjögren's syndrome disease damage index (SSDDI) score (p < 0.001) and EULAR Sjögren's syndrome disease activity index (ESSDAI) score (p = 0.010). Furthermore, the DcR3 levels were significantly lower when the pSS patients were treated with the disease-modifying anti-rheumatic drugs. At last, DcR3 expression in salivary glands of pSS patients was significantly higher than healthy controls. The DcR3 expression was significantly elevated in the pSS patients and positively correlated with the clinical characteristics, and it might be an important factor involved in the progression of pSS patients and could be a potential therapeutic target.
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