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Suppression of tumor growth and metastasis in Shkbp1 knockout mice

Cancer Gene Therapy volume 29, pages 709–721 (2022)Cite this article

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Abstract

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.

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Fig. 1: Shkbp1 was upregulated in lung cancer tissue and positively correlated with overall survival and disease-free survival in patients.
Fig. 2: Knockdown of Shkbp1 suppresses cancer cell migration and invasion.
Fig. 3: Overexpression of Shkbp1 enhance migration and invasion.
Fig. 4: Tumor growth was suppressed in Shkbp1−/− mice.
Fig. 5: Shkbp1 deficiency in immune cells of mice would decrease tumor metastasis and growth.
Fig. 6: The number of CD8+ cells are increased in Shkbp1−/− mice.

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Acknowledgements

The authors wish to thank Professor Zhao (Cancer Center of Guangzhou Medical University) for providing valuable help in inducing lung adenocarcinoma in mice with urethane.

Grant support

This work was supported by National Natural Science Foundation of China (Grant ID 81773118 and 31771578) and Key-Area Research and development Program of Guangdong Province (2019B020234003).

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Author notes

  1. The authors contributed equally: Qing Liu, Haobin Li

Authors and Affiliations

  1. Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, 510006, Guangzhou, China

    Qing Liu, Haobin Li, Mingming Yang, Ting Niu, Zeqi Zhou, Xiaohan Zhang, Xiaodong He, Lijing Wang & Jiangchao Li

  2. Jining Medical University, 272000, Jining, China

    Qing Liu

  3. Department of Pathology, Sun Yat-sen University Cancer Center, 510000, Guangzhou, China

    Yan Mei

  4. Department of Pathology, Zhuhai Branch of Traditional Chinese Medicine Hospital of Guangdong Province, 519015, Zhuhai, China

    Xiaohan Zhang

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  1. Qing Liu
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Contributions

Conception and design: JL and LW. Acquisition of data (the experiments of animal and cell lines): QL, MY, HL, YM, and ZZ. Analysis and interpretation, manuscript revision: QL, HL, XZ, JL, TN, LW. Managed transgenic mice: QL, HL, XH. Statistical analysis, statistical, computation: JL, QL, YM.

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Correspondence to Lijing Wang or Jiangchao Li.

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Liu, Q., Li, H., Yang, M. et al. Suppression of tumor growth and metastasis in Shkbp1 knockout mice. Cancer Gene Ther 29, 709–721 (2022). https://doi.org/10.1038/s41417-021-00349-x

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