Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis.
Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis.
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DOI：
10.1038/onc.2010.447
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发表时间：
2011-01-27
期刊：
影响因子：
8
通讯作者：
Wiest, J. S.
中科院分区：
文献类型：
--
作者：
DeCicco-Skinner, K. L.;Trovato, E. L.;Simmons, J. K.;Lepage, P. K.;Wiest, J. S.
肿瘤进展基因2(Tpl2)是丝裂原活化蛋白激酶信号转导通路中的一种丝氨酸/苏氨酸激酶，调节炎症通路。以前被确认为癌基因，其突变或过度表达在多种人类癌症中有报道。为了探讨其在皮肤癌发生中的作用，用dimethylbenzanthracene/12-O-tetradecanoylphorbol-13-−/−两步法建立了Tpl2TPA或野生型(WT)C57BL/6小鼠皮肤癌模型。TPL2−/−小鼠的肿瘤发生率(80%)显著高于WT小鼠(17%)，肿瘤潜伏期缩短，肿瘤总数显著增加(113vs6)。此外，经TPA处理的Tpl2−/−小鼠与WT小鼠相比，核因子-κB(NF-KappaB)活化、水肿、中性粒细胞浸润和促炎细胞因子的产生显著增加。我们研究了p38，jnk，mek和nf-κB信号通路在WT和Tpl2−/−小鼠体内和体外的作用。我们证实，Tpl2−/−小鼠的促炎作用是由于NF-κB途径的活性增加所致。这些研究表明，在化学诱导的皮肤癌发生中，Tpl2可能更多地作为一种肿瘤抑制基因而不是癌基因，因为它的缺失同时促进了肿瘤的发生和炎症的发生。
Tumor progression locus 2 (Tpl2) is a serine/threonine kinase in the mitogen-activated protein kinase signal transduction cascade known to regulate inflammatory pathways. Previously identified as an oncogene, its mutation or overexpression is reported in a variety of human cancers. To address its role in skin carcinogenesis, Tpl2−/− or wild-type (WT) C57BL/6 mice were subjected to a two-stage dimethylbenzanthracene/12-O-tetradecanoylphorbol- 13-acetate (TPA) mouse skin carcinogenesis model. Tpl2−/− mice developed a significantly higher incidence of tumors (80%) than WT mice (17%), as well as a reduced tumor latency and a significantly higher number of total tumors (113 vs 6). Moreover, Tpl2−/− mice treated with TPA experienced significantly higher nuclear factor kappaB (NF-κB) activation, edema, infiltrating neutrophils and production of proinflammatory cytokines than did WT mice. We investigated the role of the p38, JNK, MEK and NF-κB signaling pathways both in vitro and in vivo in WT and Tpl2−/− mice by using inhibitors for each of these pathways. We confirmed that the proinflammatory effect in Tpl2−/− mice was due to heightened activity of the NF-κB pathway. These studies indicate that Tpl2 may serve more as a tumor suppressor than as an oncogene in chemically induced skin carcinogenesis, with its absence contributing to both tumorigenesis and inflammation.
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