Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting both Immune Suppression and Oncogenic Cell Proliferation.
Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting both Immune Suppression and Oncogenic Cell Proliferation.
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DOI：
10.1038/s41598-018-35126-8
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发表时间：
2018-11-09
影响因子：
4.6
通讯作者：
Cutler CW
中科院分区：
文献类型：
--
作者：
Arjunan P;Meghil MM;Pi W;Xu J;Lang L;El-Awady A;Sullivan W;Rajendran M;Rabelo MS;Wang T;Tawfik OK;Kunde-Ramamoorthy G;Singh N;Muthusamy T;Susin C;Teng Y;Arce RM;Cutler CW
慢性牙周炎(CP)是一种微生物失调疾病，与口腔鳞状细胞癌(OSCCs)的风险增加有关。为了解决潜在的机制，采用了小鼠和人类细胞感染模型和人类活检样本。我们发现“基石”病原体牙龈卟啉单胞菌通过从单核细胞产生髓系来源的树突状抑制细胞(MDDSCs)来扰乱免疫监视。MDDSC通过抗凋亡途径抑制CTL并诱导FOXP3 + Treg。这一途径涉及pAKT1、pFOXO1、FOXP3、IDO1和BIM，在患有CP的人和口服感染表达牙龈假单胞菌菌株的Mfa1的小鼠中被激活。在机制上，这一途径的激活，证明FOXP3是一个直接的FOXO1靶基因，通过芯片分析证明在人CP牙龈中。癌基因而不是肿瘤抑制标志物的表达与口腔鳞状细胞癌-P中肿瘤细胞的增殖一致。牙周炎共培养。重要的是，FIMA + P.gigivalis株MFI侵袭口腔鳞状细胞，通过CXCR4诱导炎性/血管生成/致癌蛋白刺激口腔鳞状细胞增殖。抑制CXCR4可抑制PG-MFI诱导的口腔鳞状细胞癌细胞的增殖，减少致癌蛋白SDF-1/CXCR4和pAKT1-pFOXO1的表达。综上所述，牙龈假单胞菌通过MFA1和FIMA菌毛，分别通过DC-SIGN+hi/CXCR4+hi的受体-配体二次打击过程促进免疫抑制和致癌细胞的增殖，激活Pakt+hiFOXO1+hiBIM−lowFOXP3+hi和Ido+hi驱动的通路，可能影响牙周炎患者口腔癌的预后。
Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the ‘keystone’ pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + Tregs through an anti-apoptotic pathway. This pathway, involving pAKT1, pFOXO1, FOXP3, IDO1 and BIM, is activated in humans with CP and in mice orally infected with Mfa1 expressing P. gingivalis strains. Mechanistically, activation of this pathway, demonstrating FOXP3 as a direct FOXO1-target gene, was demonstrated by ChIP-assay in human CP gingiva. Expression of oncogenic but not tumor suppressor markers is consistent with tumor cell proliferation demonstrated in OSCC-P. gingivalis cocultures. Importantly, FimA + P. gingivalis strain MFI invades OSCCs, inducing inflammatory/angiogenic/oncogenic proteins stimulating OSCCs proliferation through CXCR4. Inhibition of CXCR4 abolished Pg-MFI-induced OSCCs proliferation and reduced expression of oncogenic proteins SDF-1/CXCR4, plus pAKT1-pFOXO1. Conclusively, P. gingivalis, through Mfa1 and FimA fimbriae, promotes immunosuppression and oncogenic cell proliferation, respectively, through a two-hit receptor-ligand process involving DC-SIGN+hi/CXCR4+hi, activating a pAKT+hipFOXO1+hiBIM−lowFOXP3+hi and IDO+hi- driven pathway, likely to impact the prognosis of oral cancers in patients with periodontitis.
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Keystone-Pathogen假设。
DOI：
10.1038/nrmicro2873
发表时间：
2012-10
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.1402740111
发表时间：
2014-04-08
影响因子：
11.1
作者：
Boisvert, Heike;Lorand, Laszlo;Duncan, Margaret J.
通讯作者：
Duncan, Margaret J.
影响因子：
4.3
作者：
Eke PI;Dye BA;Wei L;Slade GD;Thornton-Evans GO;Borgnakke WS;Taylor GW;Page RC;Beck JD;Genco RJ
通讯作者：
Genco RJ
影响因子：
30.5
作者：
Hou, WS;Van Parijs, L
通讯作者：
Van Parijs, L
DOI：
10.1073/pnas.1302829110
发表时间：
2013-11-12
影响因子：
11.1
作者：
Glowacki, Andrew J.;Yoshizawa, Sayuri;Little, Steven R.
通讯作者：
Little, Steven R.