Suppression of tumor growth and metastasis in Shkbp1 knockout mice
Suppression of tumor growth and metastasis in Shkbp1 knockout mice
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Shkbp1 敲除小鼠肿瘤生长和转移的抑制
DOI：
10.1038/s41417-021-00349-x
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发表时间：
2021-06-10
影响因子：
6.4
通讯作者：
Li，Jiangchao
中科院分区：
文献类型：
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作者：
Liu，Qing;Li，Haobin;Li，Jiangchao
表皮生长因子受体(EGFR)在肿瘤诊断和靶向治疗中被广泛接受。Shkbp1是EGFR的上游分子，可以阻止EGFR的降解。然而，Shkbp1在肿瘤中的作用仍有待阐明。在此，我们用化学药物在Shkbp1基因敲除小鼠的肺部诱发肿瘤，以研究Shkbp1的功能。与野生型小鼠相比，Shkbp1基因敲除小鼠的肺部肿瘤明显减少。为了进一步探讨Shkbp1在肿瘤细胞中的生物学特性和功能，我们分别建立了Shkbp1高表达和低表达的细胞系。我们的实验结果表明，Shkbp1在肺癌中的低表达显著抑制癌细胞的迁移和侵袭，而Shkbp1的过表达促进癌细胞的迁移和侵袭，这表明Shkbp1与肿瘤的迁移和侵袭密切相关。对494例配对的肿瘤组织和癌旁组织(来自TCGA数据库)的mRNA表达分析表明，Shkbp1与临床TNM分期有关。此外，组织芯片免疫组织化学(IHC)分析显示，Shkbp1也与淋巴转移有关。从机制上，我们观察到Shkbp1与上皮-间充质转化(EMT)标志物相关。更有趣的是，Shkbp1也在多种免疫细胞中表达，我们在此利用皮下移植肿瘤模型和尾静脉注射建立的转移模型来探讨Shkbp1是否会影响肿瘤的生长。结果表明，在两种肿瘤模型中，Shkbp1基因敲除都减少了肿瘤的生长。总的来说，我们的结果表明，在免疫细胞或肿瘤细胞中敲除Shkbp1可以抑制肿瘤的生长和转移。
Epidermal growth factor receptor (EGFR) is widely accepted in cancer diagnosis and targeted therapy. Shkbp1 is an upstream molecule of EGFR, which prevents EGFR degradation. However, the role of Shkbp1 in tumor remains to be clarified. Herein we induced tumor in the lungs of Shkbp1 knockout mice with chemical drugs to investigate the function of Shkbp1. Compared with wild-type mice, tumors in the lungs were significantly fewer in Shkbp1 knockout mice. To further explore the biological characteristics and functions of Shkbp1 in cancer cells, we established cell lines with overexpression and low expression of Shkbp1, respectively. Results from our experiments showed that low expression of Shkbp1 in lung cancer remarkably inhibited cancer cell migration and invasion, while overexpression of Shkbp1 promoted their migration and invasion, which indicated that Shkbp1 was closely related with tumor migration and invasion. The mRNA expression analysis of 494 matched tumor and adjacent non-tumor tissues (data derived from TCGA database) revealed that Shkbp1 was associated with the clinic TNM staging. Furthermore, immunohistochemistry (IHC) analysis of tissue microarrays showed that Shkbp1 was also correlated with lymphatic metastasis. Mechanistically, we observed that Shkbp1 was associated with epithelial–mesenchymal transition (EMT) marker. More interestingly, Shkbp1 was also expressed in a variety of immune cells, and we hereby used a subcutaneous transplantation tumor model and a metastasis model created by tail vein injection to explore whether Shkbp1 could impact tumor growth. The results showed that Shkbp1 knockout reduced tumor growth in both tumor models. In general, our results suggest that knocking out Shkbp1 in either immune cells or tumor cells could suppress tumor growth and metastasis.