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

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications Pub Date : 2024-02-26 DOI:10.1002/cac2.12527

Shiyu Zhang, Xing Jia, Haojiang Dai, Xingxin Zhu, Wenfeng Song, Suchen Bian, Hao Wu, Shinuo Chen, Yangbo Tang, Junran Chen, Cheng Jin, Mengqiao Zhou, Haiyang Xie, Shusen Zheng, Penghong Song

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Abstract

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.

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SERPINE2 通过抑制 c-Cbl 介导的表皮生长因子受体泛素化和降解，促进肝癌转移。

背景：肝癌是一种发病率和死亡率都很高的恶性肿瘤。据报道，丝氨酸蛋白家族 E 成员 2（SERPINE2）在许多肿瘤的转移中起着关键作用。本研究旨在探讨SERPINE2在肝癌转移中的潜在机制：方法：利用癌症基因组图谱数据库（TCGA），包括DNA甲基化和转录组测序数据，确定肝癌中与DNA甲基化和癌症进展相关的关键癌基因。研究人员利用 TCGA 数据和 94 对肝癌组织的 RNA 测序数据，探讨了 SERPINE2 表达与患者临床参数之间的相关性。DNA甲基化测序用于检测肝癌组织和细胞中的DNA甲基化水平。通过RNA测序、细胞因子检测、免疫沉淀（IP）和质谱（MS）检测、蛋白质稳定性检测和泛素化检测来探讨SERPINE2在肝癌转移中的调控机制。建立了患者来源的异种移植和肿瘤类器官模型，以确定SERPINE2在索拉非尼治疗肝癌中的作用：根据公共数据库筛选，SERPINE2被确定为受DNA甲基化调控的肿瘤启动子。SERPINE2在肝癌组织中的表达明显升高，并与肝癌患者的预后不良有关。SERPINE2通过增强细胞伪足形成、细胞粘附、癌相关成纤维细胞活化、细胞外基质重塑和血管生成，促进肝癌转移。IP/MS测定证实，SERPINE2通过与表皮生长因子受体（EGFR）相互作用，激活了表皮生长因子受体（EGFR）及其下游信号通路。从机理上讲，SERPINE2 通过与 E3 泛素连接酶 c-Cbl 竞争，抑制了表皮生长因子受体的泛素化，并保持了其蛋白质的稳定性。此外，索拉非尼治疗后肝癌细胞中的表皮生长因子受体被激活，而 SERPINE2 敲除诱导的表皮生长因子受体下调能显著增强索拉非尼对肝癌的疗效。此外，我们还发现敲除SERPINE2对来伐替尼治疗也有增敏作用：结论：SERPINE2通过c-Cbl介导的泛素化阻止表皮生长因子受体（EGFR）降解，从而促进肝癌转移。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research

CiteScore

25.50

自引率

4.30%

发文量

153

审稿时长

4 weeks

期刊介绍： Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.

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