The chemokine receptor CCR10 promotes inflammation-driven hepatocarcinogenesis via PI3K/Akt pathway activation.
The chemokine receptor CCR10 promotes inflammation-driven hepatocarcinogenesis via PI3K/Akt pathway activation.
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DOI：
10.1038/s41419-018-0267-9
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发表时间：
2018-02-14
影响因子：
9
通讯作者：
Zheng JF
中科院分区：
文献类型：
--
作者：
Wu Q;Chen JX;Chen Y;Cai LL;Wang XZ;Guo WH;Zheng JF
G蛋白偶联受体（GPCR）相关蛋白质失调，GPCR CC-趋化因子受体10（CCR 10）在炎症驱动的HCC中显著上调。然而，CCR 10在炎症驱动的肝癌发生中的作用尚不清楚。本研究的目的是评估CCR 10在炎症驱动的肝癌发生中的作用。通过靶向基因表达微阵列筛选GPCR家族基因表达的改变，我们发现CCR 10在从炎症驱动的人HCC肿瘤和匹配的癌旁组织分离的肝细胞中显著上调。四氯化碳（CCl 4）诱导的和二乙基亚硝胺（DEN）诱导的炎性肝癌小鼠模型显示出显着的肝细胞TNF和CCR 10上调。外源性TNF应用于HepG 2和LO 2细胞系以及野生型（WT）小鼠显著上调肝细胞CCR 10表达，Akt磷酸化，PCNA表达和肝细胞增殖。此外，外源性TNF显着上调天然CCR 10配体激动剂CCL 28从两个细胞系的分泌。转基因CCR 10基因敲除（CCR 10 KO）在DEN治疗的小鼠肝细胞凋亡水平显着增加，并显着降低代偿性肝细胞增殖，但不影响上游TNF的表达。此外，DEN治疗的CCR 10 KO小鼠显示出显著较低的肝重/体重比、显著较低的肝肿瘤发生率和显著较小的肿瘤。此外，外源性CCR 10表达显著提高Balb/c裸鼠中异种移植瘤的生长。在体外，CCR 10转染或CCL 28处理的HepG 2和LO 2细胞系显着增加Akt磷酸化，PCNA表达和细胞增殖，而CCR 10沉默或Akt抑制产生相反的效果。在体内，从DEN治疗的CCR 10 KO小鼠的HCC肿瘤组织和匹配的癌旁组织中分离的肝细胞显示相对于WT肝细胞显著较低的Akt磷酸化和PCNA表达。总之，炎症诱导的TNF促进肝细胞CCR 10表达和下游PI 3 K/Akt介导的肝癌发生。CCR 10似乎在TNF刺激和下游PI 3 K/Akt通路激活之间起联系作用，并显示出作为炎症驱动的HCC的潜在治疗靶点的前景。
G-protein-coupled receptor (GPCR)-related proteins are dysregulated and the GPCR CC-chemokine receptor 10 (CCR10) is significantly upregulated in inflammation-driven HCC. However, CCR10′s role in inflammation-driven hepatocarcinogenesis remains unknown. The aim of this study was to evaluate the role of CCR10 in inflammation-driven hepatocarcinogenesis. Via a targeted gene expression microarray screening alterations in GPCR family gene expression, we found CCR10 to be significantly upregulated in hepatocytes isolated from inflammation-driven human HCC tumors and matching paracancerous tissues. Tetrachloromethane (CCl4)-induced and diethylnitrosamine (DEN)-induced murine models of inflammatory hepatocarcinogenesis displayed significant hepatocellular TNF and CCR10 upregulation. Exogenous TNF applied to HepG2 and LO2 cell lines as well as wild-type (WT) mice significantly upregulated hepatocellular CCR10 expression, Akt phosphorylation, PCNA expression, and hepatocellular proliferation. Additionally, exogenous TNF significantly upregulated secretion of the natural CCR10 ligand-agonist CCL28 from both cell lines. Transgenic CCR10-knockout (CCR10 KO) in DEN-treated mice significantly increased hepatocellular apoptosis levels and significantly lowered compensatory hepatocellular proliferation but did not affect upstream TNF expression. In addition, DEN-treated CCR10 KO mice showed a significantly lower liver weight/body weight ratio, significantly lower liver tumor incidence, and significantly smaller tumors. Moreover, exogenous CCR10 expression significantly raised xenograft tumor growth in Balb/c nude mice. In vitro, CCR10 transfection or CCL28 treatment in HepG2 and LO2 cell lines significantly increased Akt phosphorylation, PCNA expression, and cell proliferation, while CCR10 silencing or Akt inhibition produced the opposite effects. In vivo, hepatocytes isolated from HCC tumor tissue and matching paracancerous tissue in DEN-treated CCR10 KO mice showed significantly lower Akt phosphorylation and PCNA expression relative to WT hepatocytes. In conclusion, inflammation-induced TNF promotes hepatocellular CCR10 expression and downstream PI3K/Akt-mediated hepatocarcinogenesis. CCR10 appears to function as a linkage between TNF stimulation and downstream PI3K/Akt pathway activation and shows promise as a potential therapeutic target for inflammation-driven HCC.
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影响因子：
50.3
作者：
Nakagawa H;Umemura A;Taniguchi K;Font-Burgada J;Dhar D;Ogata H;Zhong Z;Valasek MA;Seki E;Hidalgo J;Koike K;Kaufman RJ;Karin M
通讯作者：
Karin M
影响因子：
4.5
作者：
Alexeev, Vitali;Donahue, Adele;Uitto, Jouni;Igoucheva, Olga
通讯作者：
Igoucheva, Olga
影响因子：
4.8
作者：
Rajagopal, Sudarshan;Bassoni, Daniel L.;Wehrman, Tom S.
通讯作者：
Wehrman, Tom S.
影响因子：
4.4
作者：
Eksteen, Bertus;Miles, Alice;Adams, David H.
通讯作者：
Adams, David H.
影响因子：
8.4
作者：
Simonetti, O;Goteri, G;Offidani, A
通讯作者：
Offidani, A