Tpl2 in Intestinal Tumorigenesis

Tpl2 在肠道肿瘤发生中的作用

• 批准号: 7785303
• 负责人: PHILIP N. TSICHLIS
• 金额: $ 32.99万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7785303
• 关键词: Ablation; Acceleration; Address; Animal Model; Biology; Breast Adenocarcinoma; Cell Count; Cell Line; Colon Carcinoma; Colorectal Cancer; Data; Defect; Disease; Down-Regulation; Epithelial Cells; Event; Exhibits; Functional disorder; Genes; Genetic; Human; Inflammation; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Inflammatory disease of the intestine; Interleukin-10; Intestinal Mucosa; Intestinal Polyps; Intestines; Knockout Mice; Link; Lymphoma; Malignant Epithelial Cell; Malignant Neoplasms; Modeling; Mus; Mutation; Paneth Cells; Pathway interactions; Phosphotransferases; Polyps; Proto-Oncogenes; Provirus Integration; Regulation; Relative (related person); Retroviridae; Rodent; Role; Signal Transduction; Staging; Stem cells; Therapeutic Intervention; Tumor Cell Biology; Tumor Suppressor Genes; Work; antimicrobial peptide; expectation; human FRAP1 protein; intestinal crypt; intestinal epithelium; macrophage; public health relevance; tool; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): The proto-oncogene encoding the Tpl2 kinase is activated by provirus integration in retrovirus-induced rodent lymphomas and mammary adenocarcinomas. Here, we present evidence that Tpl2 also functions as a tumor suppressor gene in the intestinal epithelia. To determine the role of Tpl2 in Apcmin-induced tumorigenesis, we crossed the Apcmin mutation into the Tpl2-/- genetic background. Contrary to expectation, Tpl2-/-/ Apcmin/+ mice exhibited a 5-fold increase in the number of intestinal polyps and a significant acceleration in tumorigenesis relative to their Tpl2+/+/Apcmin/+ littermates. The high number of polyps in Tpl2-/-/ Apcmin/+, relative to Tpl2+/+/Apcmin/+ mice suggested that Tpl2 ablation promotes tumor initiation. Since the earliest genetic change responsible for tumor initiation is the loss of heterozygocity (LOH) in the APC locus, it follows that Tpl2 ablation promotes LOH. This could be caused by several mechanisms. One possibility is that Tpl2 ablation increases the number of intestinal stem cells that may be the targets of LOH. Given that the Wnt pathway promotes the cycling of stem cells, we hypothesized that Tpl2 ablation may cause an increase in stem cell numbers, by stimulating Wnt signaling. Studies presented here however showed that, although Tpl2 has the potential to inhibit Wnt signaling in several types of epithelial cells, Tpl2 ablation does not increase the number of stem cells in the intestinal crypts. Further studies revealed that Tpl2 ablation promotes intestinal inflammation, which is also known to stimulate tumor initiation. A search for the causes of inflammation revealed that Tpl2 ablation causes a Paneth cell defect, characterized by significant downregulation of genes encoding antimicrobial peptides. The same search revealed that inhibition of TLR signals that may be transduced via Tpl2, stimulates the activity of the canonical Wnt pathway in macrophages and that the levels of IL-10 in the intestinal mucosa of Tpl2-/- mice are decreased. The role of Tpl2 however, may not be restricted to tumor initiation. Our preliminary data indeed provide strong evidence that Tpl2 ablation may also contribute to the late stages of oncogenesis. Tpl2 ablation may modulate the biology of tumor cells induced by the ablation of APC by targeting the Wnt pathway, or perhaps other interacting pathways. Alternatively, it may target Akt and mTOR, as suggested by our recent studies on human colon carcinoma cell lines. Work proposed in this application will focus on the role of Tpl2 in the regulation of pre-LOH and post-LOH events in intestinal tumorigenesis induced by APC mutations. PUBLIC HEALTH RELEVANCE: Our preliminary data, interpreted in the context of genetic studies in humans, indicate that the Tpl2 knockout mouse is an excellent animal model for inflammatory bowel disease (IBD). The same data provide a strong link between inflammation and cancer. The Tpl2 ablation model therefore, provides a valuable tool to mechanistically address the pathophysiology of IBD and colorectal cancer and to identify new targets for therapeutic intervention in these diseases.

描述（由申请人提供）：编码Tpl2激酶的原癌基因在逆转录病毒诱导的啮齿动物淋巴瘤和乳腺腺癌中被原病毒整合激活。在这里，我们提出证据表明Tpl2在肠上皮中也作为肿瘤抑制基因起作用。为了确定Tpl2在Apcmin诱导的肿瘤发生中的作用，我们将Apcmin突变与Tpl2-/-遗传背景交叉。与预期相反，与Tpl2+/+/Apcmin/+的小鼠相比，Tpl2-/-/ Apcmin/+的小鼠肠息肉数量增加了5倍，肿瘤发生速度明显加快。与Tpl2+/+/Apcmin/+小鼠相比，Tpl2-/-/ Apcmin/+小鼠息肉数量较多，提示Tpl2消融促进肿瘤发生。由于最早导致肿瘤发生的遗传变化是APC基因座的杂合子缺失（LOH），因此Tpl2消融促进LOH。这可能是由几种机制引起的。一种可能性是Tpl2消融增加了可能成为LOH靶点的肠道干细胞的数量。鉴于Wnt通路促进干细胞循环，我们假设Tpl2消融可能通过刺激Wnt信号传导导致干细胞数量增加。然而，本研究显示，尽管Tpl2有可能抑制几种类型上皮细胞中的Wnt信号，但Tpl2消融并不会增加肠隐窝中干细胞的数量。进一步的研究表明，Tpl2消融促进肠道炎症，这也刺激肿瘤的发生。对炎症原因的研究表明，Tpl2消融导致Paneth细胞缺陷，其特征是编码抗菌肽的基因显著下调。同样的研究表明，抑制可能通过Tpl2转导的TLR信号，可以刺激巨噬细胞中典型Wnt通路的活性，并且Tpl2-/-小鼠肠黏膜中IL-10水平降低。然而，Tpl2的作用可能并不局限于肿瘤的发生。我们的初步数据确实提供了强有力的证据，证明Tpl2消融也可能有助于晚期肿瘤的发生。Tpl2消融可能通过靶向Wnt通路或其他相互作用通路来调节APC消融诱导的肿瘤细胞的生物学。或者，根据我们最近对人结肠癌细胞系的研究，它可能靶向Akt和mTOR。本研究将重点研究Tpl2在APC突变诱导的肠道肿瘤发生中对loh前和loh后事件的调控作用。