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Suppression of tumor growth and metastasis in Shkbp1 knockout mice
Qing Liu1,2, Haobin Li1, Mingming Yang1
1Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, 510006, Guangzhou, China.
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.
Insights
Knocking out Shkbp1 significantly reduces lung tumors and metastasis in mice by inhibiting cancer cell migration and invasion. This suggests Shkbp1 plays a key role in tumor progression and offers a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Epidermal growth factor receptor (EGFR) is crucial for cancer diagnosis and therapy.
- Shkbp1 regulates EGFR degradation, but its role in tumor development is unclear.
- Understanding Shkbp1's function is vital for developing new cancer treatments.
Purpose of the Study:
- To investigate the role of Shkbp1 in tumor formation, migration, and invasion.
- To explore the association of Shkbp1 with clinical cancer staging and metastasis.
- To determine the impact of Shkbp1 on tumor growth in vivo.
Main Methods:
- Generated Shkbp1 knockout mice and induced lung tumors using chemical agents.
- Established cancer cell lines with altered Shkbp1 expression (overexpression and knockdown).
- Analyzed tumor tissues (TCGA database, tissue microarrays) and utilized in vivo tumor models.
Main Results:
- Shkbp1 knockout mice exhibited significantly fewer lung tumors compared to wild-type.
- Reduced Shkbp1 expression inhibited cancer cell migration and invasion; overexpression promoted it.
- Shkbp1 expression correlated with TNM staging, lymphatic metastasis, and epithelial-mesenchymal transition (EMT) markers.
- Shkbp1 knockout suppressed tumor growth in subcutaneous and metastasis models.
Conclusions:
- Shkbp1 promotes tumor cell migration, invasion, and metastasis.
- Shkbp1 is linked to clinical progression and EMT in cancer.
- Targeting Shkbp1 in tumor or immune cells can suppress tumor growth and metastasis.
