SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation.

Publisher: Wiley Country of Publication: United States NLM ID: 101723675 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2523-3548 (Electronic) Linking ISSN: 25233548 NLM ISO Abbreviation: Cancer Commun (Lond) Subsets: MEDLINE

Publication: 2020- : [Hoboken, NJ] : Wiley
Original Publication: [London] : BioMed Central, [2018]-

Liver Neoplasms*/genetics ; Serpin E2*/genetics ; Serpin E2*/metabolism; Humans ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Proto-Oncogene Proteins c-cbl/genetics ; Proto-Oncogene Proteins c-cbl/metabolism ; Sorafenib ; Ubiquitination

Background: Liver cancer is a malignancy with high morbidity and mortality rates. Serpin family E member 2 (SERPINE2) has been reported to play a key role in the metastasis of many tumors. In this study, we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.
Methods: The Cancer Genome Atlas database (TCGA), including DNA methylation and transcriptome sequencing data, was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver cancer. Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clinical parameters of patients. DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells. RNA sequencing, cytokine assays, immunoprecipitation (IP) and mass spectrometry (MS) assays, protein stability assays, and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis. Patient-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.
Results: Based on the public database screening, SERPINE2 was identified as a tumor promoter regulated by DNA methylation. SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer. SERPINE2 promoted liver cancer metastasis by enhancing cell pseudopodia formation, cell adhesion, cancer-associated fibroblast activation, extracellular matrix remodeling, and angiogenesis. IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor (EGFR) and its downstream signaling pathways by interacting with EGFR. Mechanistically, SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase, c-Cbl. Additionally, EGFR was activated in liver cancer cells after sorafenib treatment, and SERPINE2 knockdown-induced EGFR downregulation significantly enhanced the therapeutic efficacy of sorafenib against liver cancer. Furthermore, we found that SERPINE2 knockdown also had a sensitizing effect on lenvatinib treatment.
Conclusions: SERPINE2 promoted liver cancer metastasis by preventing EGFR degradation via c-Cbl-mediated ubiquitination, suggesting that inhibition of the SERPINE2-EGFR axis may be a potential target for liver cancer treatment.
(© 2024 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center.)

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2020C04003 Department of Science and Technology of Zhejiang Province; zz202302 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; 2019-I2M-5-030 Chinese Academy of Medical Sciences; 82070652 National Natural Science Foundation of China; 81870434 National Natural Science Foundation of China; JNL-2022007B Jinan Microecological Biomedicine Shandong Laboratory

Keywords: DNA methylation; EGFR; SERPINE2; c‐Cbl; liver cancer; metastasis; ubiquitination

EC 2.7.10.1 (EGFR protein, human)
EC 2.7.10.1 (ErbB Receptors)
EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl)
0 (Serpin E2)
0 (SERPINE2 protein, human)
9ZOQ3TZI87 (Sorafenib)
EC 6.3.2.- (CBL protein, human)

Date Created: 20240226 Date Completed: 20240325 Latest Revision: 20240327

20250114

PMC10958675

10.1002/cac2.12527

38407942