SERPINE2 Promotes Liver Cancer Metastasis by Inhibiting c-Cbl–Mediated EGFR Ubiquitination and Degradation

Background: Liver cancer is a malignant tumor with high morbidity and mortality. Serpin Family E Member 2 (SERPINE2) has been reported to play a key role in the metastasis of many tumors; however, the potential mechanism of SERPINE2 in liver cancer metastasis has not been fully explored.Methods: Public databases and DNA methylation sequencing were used to explore the correlation between SERPINE2 expression and DNA methylation and clinical parameters of patients. RNA sequencing, IP assay, protein stability assay, and ubiquitination assay were used to explore the regulatory mechanism of SERPINE2 in liver cancer.Findings: We identified SERPINE2 as a tumor metastasis-promoting gene regulated by DNA methylation. ​SERPINE2 expression was higher in liver cancer and was associated with the dismal prognosis of patients. Mechanistically, SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the c-Cbl. Additionally, SERPINE2 knockdown significantly enhanced the therapeutic efficacy of sorafenib in liver cancer.Interpretation: SERPINE2 promotes liver cancer metastasis by preventing EGFR degradation from c-Cbl–mediated ubiquitination, suggesting that inhibition of the SERPINE2-EGFR axis may be a potential target for liver cancer treatment.Funding: This work was supported by the National Natural Science Foundation of China (No. 82070652, No. 81870434), the Key Research and Development Plan of Zhejiang Province (No. 2020C04003), the Research Unit Project of the Chinese Academy of Medical Sciences (2019-I2M-5-030), the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022007B) and the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202302).Declaration of Interest: The authors declare no competing interests.Ethical Approval: All tissue samples were obtained from patients with liver cancer who underwent surgery at the First Affiliated Hospital of Zhejiang University School of Medicine. Written informed consent was obtained from each patient. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine. This study was approved by the Animal Care Committee of Zhejiang University and was conducted in strict accordance with the National Institutes of Health Animal Care and Use Guidelines.