文章：

表皮生长因子受体/人表皮生长因子受体2通路激活增强促进Tpl2基因敲除小鼠皮肤肿瘤发生

Increased EGFR/HER2 Pathway Activation Contributes to Skin Tumorigenesis inTpl2−/−Mice

原文发布日期：18 October 2025

DOI: 10.3390/cancers17203362

类型: Article

开放获取: 是

英文摘要：

Background:The mitogen-activated protein kinase (MAPK) signaling pathway is frequently dysregulated in cutaneous squamous cell carcinoma (cSCC). Tumor progression locus 2 (Tpl2), a serine/threonine protein kinase within the MAPK family, regulates cellular proliferation, survival, and inflammatory responses. Loss ofTpl2activates compensatory signaling cascades, driving increased papilloma and cSCC development. In this study we examined whether dysregulated ErbB signaling contributes to the enhanced tumor burden found inTpl2−/−mice.Methods: To evaluate whether aberrant ErbB signaling drives tumorigenesis inTpl2−/−mice, wild-type (Tpl2+/+) and Tpl2−/−mice were subjected to a two-stage chemical carcinogenesis protocol for 48 weeks. A subset of mice received Gefitinib (an EGFR inhibitor) or Lapatinib (a HER2 inhibitor) in their diet.Results: We found thatTpl2ablation increases gene expression of EGFR, HER2, and HER3, while baseline protein levels remain unchanged betweenTpl2genotypes. To investigate the possibility of microRNA (miR)-mediated post-transcriptional regulation of EGFR, HER2, and HER3, we measured ErbB-related miR expression in keratinocytes. We found that HER2/3-related miRs 205 and 21 are increased inTpl2−/−keratinocytes. Further,Tpl2loss enhances p-EGFR, EGFR, and HER2 protein expression in papillomas. and HER2-related microRNAs (miRs) 205 and 21 in keratinocytes, and enhances p-EGFR, EGFR, and HER2 protein expression in papillomas.Tpl2−/−mice developed 12-fold more papillomas and 4-fold more cSCCs compared toTpl2+/+animals. Treatment with Gefitinib or Lapatinib reduced papilloma numbers by 88% and 50%, respectively, while restoring cSCC numbers toTpl2+/+levels.Conclusions: These findings indicate that ErbB targeting represents a promising therapeutic strategy for cSCCs arising from MAPK pathway dysregulation.

摘要翻译： 

背景：丝裂原活化蛋白激酶（MAPK）信号通路在皮肤鳞状细胞癌（cSCC）中常出现失调。肿瘤进展位点2（Tpl2）作为MAPK家族中的丝氨酸/苏氨酸蛋白激酶，调控细胞增殖、存活及炎症反应。Tpl2缺失会激活代偿性信号级联反应，从而促进乳头状瘤和cSCC的发展。本研究旨在探讨ErbB信号通路失调是否与Tpl2−/−小鼠中观察到的肿瘤负荷增加有关。 方法：为评估异常ErbB信号是否驱动Tpl2−/−小鼠的肿瘤发生，对野生型（Tpl2+/+）和Tpl2−/−小鼠进行了为期48周的两阶段化学致癌实验。部分小鼠通过饮食摄入吉非替尼（EGFR抑制剂）或拉帕替尼（HER2抑制剂）。 结果：研究发现Tpl2缺失会上调EGFR、HER2和HER3的基因表达，而两种Tpl2基因型小鼠的基础蛋白水平无显著差异。为探究microRNA（miR）介导的EGFR、HER2和HER3转录后调控机制，我们检测了角质形成细胞中ErbB相关miR的表达水平。结果显示，Tpl2−/−角质形成细胞中HER2/3相关miR-205和miR-21表达升高。此外，Tpl2缺失增强了乳头状瘤中p-EGFR、EGFR和HER2的蛋白表达。与Tpl2+/+小鼠相比，Tpl2−/−小鼠的乳头状瘤数量增加12倍，cSCC数量增加4倍。吉非替尼或拉帕替尼治疗分别使乳头状瘤数量减少88%和50%，同时使cSCC数量恢复至Tpl2+/+小鼠水平。 结论：这些发现表明，针对ErbB信号通路的靶向治疗是MAPK通路失调所致cSCC的潜在治疗策略。

原文链接：

Increased EGFR/HER2 Pathway Activation Contributes to Skin Tumorigenesis inTpl2−/−Mice