Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis
Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis
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DOI：
10.1172/jci63917
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发表时间：
2012-11-01
影响因子：
15.9
通讯作者：
Kollias, George
中科院分区：
文献类型：
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作者：
Koliaraki, Vasiliki;Roulis, Manolis;Kollias, George
肿瘤微环境在结肠炎相关癌症（CAC）中起着重要作用。肠肌成纤维细胞（IMFs）是肠固有层中的细胞，分泌已知调节癌变的因子;然而，影响CAC的IMFs和信号通路的生理作用仍然未知。肿瘤进展基因座2（Tpl 2）是调节炎性和致癌途径的MAPK。在这项研究中，我们使用突变小鼠中Tp 12的完全和组织特异性消融来解决Tp 12在CAC中的作用。与野生型小鼠相比，Tp 12缺陷型小鼠在氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）施用后在炎症负荷方面没有表现出显著差异;然而，突变小鼠发展出显著增加的肿瘤数量和大小，与增强的上皮增殖和减少的细胞凋亡相关。在IMF中，但不是在肠上皮细胞或骨髓细胞中，Tpl 2的细胞特异性消融赋予了对腺癌形成的类似易感性。Tp 12缺陷型IMF上调HGF的产生，并且对TGF-β 3对HGF的负调节变得不太敏感。体内抑制HGF介导的c-Met活化阻断了Tpl 2缺陷小鼠中早期增强的结肠发育不良，表明Tpl 2通常抑制HGF/c-Met途径。这些发现确立了Tpl 2在调节HGF产生和抑制上皮肿瘤发生中的间充质特异性作用。
The tumor microenvironment plays a significant role in colitis-associated cancer (CAC). Intestinal myofibroblasts (IMFs) are cells in the intestinal lamina propria secreting factors that are known to modulate carcinogenesis; however, the physiological role of IMFs and signaling pathways influencing CAC have remained unknown. Tumor progression locus 2 (Tpl2) is a MAPK that regulates inflammatory and oncogenic pathways. In this study we addressed the role of Tpl2 in CAC using complete and tissue-specific ablation of Tpl2 in mutant mice. Tpl2-deficient mice did not exhibit significant differences in inflammatory burdens following azoxymethane (AOM)/dextran sodium sulfate (DSS) administration compared with wild-type mice; however, the mutant mice developed significantly increased numbers and sizes of tumors, associated with enhanced epithelial proliferation and decreased apoptosis. Cell-specific ablation of Tpl2 in IMFs, but not in intestinal epithelial or myeloid cells, conferred a similar susceptibility to adenocarcinoma formation. Tpl2-deficient IMFs upregulated HGF production and became less sensitive to the negative regulation of HGF by TGF-beta 3. In vivo inhibition of HGF-mediated c-Met activation blocked early, enhanced colon dysplasia in Tpl2-deficient mice, indicating that Tpl2 normally suppresses the HGF/c-Met pathway. These findings establish a mesenchyme-specific role for Tpl2 in the regulation of HGF production and suppression of epithelial tumorigenesis.