系统筛选蛋白编码基因表达，发现 VWF 是蒽环类化疗药物加重乳腺癌转移的一个潜在关键调节因子。
Systematic screening of protein-coding gene expression identified VWF as a potential key regulator in anthracycline-based chemotherapy-exacerbated metastasis of breast cancer.
机构信息
Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China.
Changchun Medical College, Changchun, 130031, China.
出版信息
BMC Cancer. 2024 Oct 8;24(1):1243. doi: 10.1186/s12885-024-12999-9.
BACKGROUND
Breast cancer is the most commonly diagnosed cancer worldwide. Although major treatments represented by chemotherapy have shown effectiveness at the initial period, recurrence and metastasis still occur later after treatments. The alternation of the tumor microenvironment by chemotherapy is confirmed as a trigger of the elevated proliferation and migration of the remaining tumor cells.
METHODS
Using bioinformatic methods, differential gene expression analysis was used to determine DEGs between post-chemotherapy and pre-chemotherapy samples of breast cancer patients, followed by survival analysis and ELISA analysis of the potential key genes. An in vitro model of 2 breast cancer cells lines was used to demonstrate the role of VWF in the evasion and migration of breast cancer cells, using cell migration, evasion and wound healing assays, PCR and molecular docking analysis.
RESULTS
19 hub genes were further identified using GO and KEGG pathway analyses and WGCNA. The 5 secreted protein-coding genes with reported carcinogenesis effects (VWF, SVEP1, DPT, ADIPOQ, and LPL) were further analyzed in breast cancer patients and VWF was identified as a potential key regulator in the anthracycline-based chemotherapy-exacerbated metastasis. It was further confirmed that anthracycline-based chemotherapeutics doxorubicin exacerbated VWF upregulation and the evasion and migration of breast cancer cells. Based on molecular docking analysis and previous study, berberine was used as an inhibitor of VWF, and showed an effective inhibition of the doxorubicin-exacerbated VWF upregulation, migration and evasion in breast cancer.
CONCLUSIONS
Doxorubicin-exacerbated evasion and migration through VWF upregulation. Berberine as an inhibitor of VWF was able to reversed the doxorubicin-exacerbated VWF upregulation and evasion and migration in breast cancer cells.
背景
乳腺癌是全球最常见的癌症。尽管以化疗为代表的主要治疗方法在初期表现出了疗效，但治疗后仍会出现复发和转移。化疗引起的肿瘤微环境改变被证实是触发剩余肿瘤细胞增殖和迁移的一个因素。
方法
使用生物信息学方法，对乳腺癌患者化疗前后样本的差异基因表达进行分析，然后进行潜在关键基因的生存分析和 ELISA 分析。利用 2 种乳腺癌细胞系的体外模型，通过细胞迁移、逃逸和伤口愈合试验、PCR 和分子对接分析，证明 VWF 在乳腺癌细胞逃逸和迁移中的作用。
结果
通过 GO 和 KEGG 通路分析和 WGCNA，进一步鉴定了 19 个枢纽基因。进一步分析了具有报道的致癌作用的 5 个分泌蛋白编码基因（VWF、SVEP1、DPT、ADIPOQ 和 LPL）在乳腺癌患者中的作用，发现 VWF 是蒽环类化疗药物加剧转移的潜在关键调节因子。进一步证实，蒽环类化疗药物阿霉素加剧了 VWF 的上调以及乳腺癌细胞的逃逸和迁移。基于分子对接分析和先前的研究，小檗碱被用作 VWF 的抑制剂，显示出对阿霉素加剧的 VWF 上调、乳腺癌细胞迁移和逃逸的有效抑制作用。
结论
阿霉素通过上调 VWF 加剧了逃逸和迁移。VWF 的抑制剂小檗碱能够逆转阿霉素加剧的 VWF 上调以及乳腺癌细胞的逃逸和迁移。
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