Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis.
Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis.
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Cystathionine β-合酶介导的 PRRX2/IL-6/STAT3 失活抑制 Tregs 浸润并诱导细胞凋亡，从而抑制 HCC 癌变。
DOI：
10.1136/jitc-2021-003031
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发表时间：
2021-08
影响因子：
10.9
通讯作者：
Shi YH
中科院分区：
文献类型：
--
作者：
Zhou YF;Song SS;Tian MX;Tang Z;Wang H;Fang Y;Qu WF;Jiang XF;Tao CY;Huang R;Zhou PY;Zhu SG;Zhou J;Fan J;Liu WR;Shi YH
肝细胞癌（HCC）是一种以炎症和免疫发病机制为特征的疾病。越来越多的证据表明，胱硫醚β-合酶/硫化氢（CBS/H2S）轴参与炎症的调节。然而，CBS在HCC发展和免疫逃避中的作用尚未得到系统研究，其潜在机制仍然难以捉摸。本研究旨在探讨CBS在肝癌肿瘤细胞和肿瘤微环境中的作用。收集236例肝癌标本，检测CBS、切割的Caspase-3和配对相关同源框2（PRRX 2）的表达以及免疫细胞数量。采用肝癌细胞系检测CBS对体外细胞活力、凋亡和信号传导的影响。采用CBS杂合子基因敲除小鼠、C57 BL/6小鼠、裸鼠和非肥胖型糖尿病重症联合免疫缺陷小鼠研究CBS的体内功能。CBS在HCC中表达下调，CBS低表达预示HCC患者预后不良。CBS过表达在体外显著促进细胞凋亡，在体内抑制肿瘤生长。Cbs/H2S轴的激活也减少了肿瘤浸润性Tregs的丰度，而Cbs缺乏促进Tregs介导的免疫逃避，并促进Cbs杂合敲除小鼠的肿瘤生长。CBS通过抑制IL-6/STAT 3通路，促进肿瘤细胞中Caspase-3的表达，抑制Foxp 3的表达。作为IL-6的转录因子，PRRX 2被CBS降低。此外，miR-24- 3 p被证明是HCC中CBS的上游抑制因子。我们的研究结果表明CBS通过灭活PRRX 2/IL-6/STAT 3通路在HCC中发挥抗肿瘤作用，这可能成为HCC临床免疫治疗的潜在靶点。
Hepatocellular carcinoma (HCC) is characterized by inflammation and immunopathogenesis. Accumulating evidence has shown that the cystathionine β-synthase/hydrogen sulfide (CBS/H2S) axis is involved in the regulation of inflammation. However, roles of CBS in HCC development and immune evasion have not been systematically investigated, and their underlying mechanisms remain elusive. Here, we investigated the roles of CBS in tumor cells and tumor microenvironment of HCC. 236 HCC samples were collected to detect the expression of CBS, cleaved Caspase-3 and paired related homeobox 2 (PRRX2) and the number of immune cells. HCC cell lines were employed to examine the effects of CBS on cellular viability, apoptosis and signaling in vitro. Cbs heterozygous knockout mice, C57BL/6 mice, nude mice and non-obese diabetic severe combined immunodeficiency mice were used to investigate the in vivo functions of CBS. Downregulation of CBS was observed in HCC, and low expression of CBS predicted poor prognosis in HCC patients. CBS overexpression dramatically promoted cellular apoptosis in vitro and inhibited tumor growth in vivo. Activation of the Cbs/H2S axis also reduced the abundance of tumor-infiltrating Tregs, while Cbs deficiency promoted Tregs-mediated immune evasion and boosted tumor growth in Cbs heterozygous knockout mice. Mechanistically, CBS facilitated the expression cleaved Caspase-3 in tumor cells, and on the other hand, suppressed Foxp3 expression in Tregs via inactivating IL-6/STAT3 pathway. As a transcription factor of IL-6, PRRX2 was reduced by CBS. Additionally, miR-24-3p was proven to be an upstream suppressor of CBS in HCC. Our results indicate the antitumor function of CBS in HCC by inactivation of the PRRX2/IL-6/STAT3 pathway, which may serve as a potential target for HCC clinical immunotherapy.
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DOI：
10.1007/164_2017_72
发表时间：
2018-01-01
期刊：
TARGETING TRAFFICKING IN DRUG DEVELOPMENT
影响因子：
--
作者：
Majtan, Tomas;Pey, Angel L.;Kraus, Jan P.
通讯作者：
Kraus, Jan P.
影响因子：
81.5
作者：
Llovet, Josep M.;Zucman-Rossi, Jessica;Gores, Gregory
通讯作者：
Gores, Gregory
影响因子：
50.3
作者：
Kortylewski M;Xin H;Kujawski M;Lee H;Liu Y;Harris T;Drake C;Pardoll D;Yu H
通讯作者：
Yu H
影响因子：
32.4
作者：
Noy, Roy;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.
影响因子：
4.2
作者：
Kim, Jongmin;Hong, Seok Joo;Kim, Dae Shick
通讯作者：
Kim, Dae Shick