骨桥蛋白通过激活 PI3k/Akt/mTOR 通路促进三阴性乳腺癌的肿瘤生长和转移以及 GPX4 介导的抗脂质过氧化。
Osteopontin promotes tumor growth and metastasis and GPX4-mediated anti-lipid peroxidation in triple-negative breast cancer by activating the PI3k/Akt/mTOR pathway.
机构信息
Department of Thyroid and Breast Surgery, Nanyang Central Hospital, No. 312 Gongnong Road, Wancheng District, Nanyang City, 473005, Henan Province, China.
Xinxiang Medical University, Xinxiang City, 453003, Henan Province, China.
出版信息
J Cancer Res Clin Oncol. 2024 Mar 25;150(3):155. doi: 10.1007/s00432-024-05658-w.
PURPOSE
Triple-negative breast cancer (TNBC) features high aggressiveness, metastasis rate, drug resistance as well as poor prognosis. Osteopontin (OPN) is a key protein in the process of osteogenesis and has emerged as a new tumor marker in recent years.
METHODS
Cell viability was tested with the CCK-8 kit. Transwell and wound healing were adopted to test cell invasive and migratory abilities. Tumor sphere formation was detected by tumor sphere formation assay. Human umbilical vein endothelial cell (HUVEC) tube formation assay was used to measure the angiogenesis of tumor cells. Western blot was applied for the estimation of the expression of cancer stem cell markers, angiogenesis-, signaling pathway-related proteins as well as OPN. Bioinformatics tools predicted OPN expression in breast cancer tissues. The levels of oxidative stress-related markers were assessed with ELISA. Following the overexpression of OPN in MD-MB-436 cells and the addition of the PI3K/AKT/mTOR pathway inhibitor LY294002, the aforementioned functional experiments were implemented again to investigate the mechanism. Finally, in vivo experiments of tumor-bearing mice were performed for further verification.
RESULTS
The proliferative, invasive, migratory and tumor sphere formation capabilities as well as angiogenesis of TNBC cells were conspicuously increased in contrast to non-TNBC cell lines. OPN expression in TNBC tissues and cells was dramatically enhanced. OPN upregulation significantly elevated cell proliferative, invasive and migratory capabilities as well as tumor sphere formation and angiogenesis. The mechanism might be achieved by activating PI3K/AKT/mTOR signaling to regulate glutathione peroxidase 4 (GPX4)-mediated anti-lipid peroxidation.
CONCLUSION
OPN promoted tumor sphere formation and angiogenesis in TNBC by activating the PI3K/AKT/mTOR pathway to regulate GPX4-mediated anti-lipid peroxidation levels.
目的
三阴性乳腺癌（TNBC）具有侵袭性高、转移率高、耐药性强、预后差等特点。骨桥蛋白（OPN）是成骨过程中的关键蛋白，近年来已成为新的肿瘤标志物。
方法
用 CCK-8 试剂盒检测细胞活力。采用 Transwell 和划痕实验检测细胞侵袭和迁移能力。通过肿瘤球形成实验检测肿瘤球形成能力。用人脐静脉内皮细胞（HUVEC）管形成实验测量肿瘤细胞的血管生成能力。Western blot 用于评估癌症干细胞标志物、血管生成、信号通路相关蛋白和 OPN 的表达。生物信息学工具预测乳腺癌组织中 OPN 的表达。用 ELISA 评估氧化应激相关标志物的水平。在 MD-MB-436 细胞中转染 OPN 并添加 PI3K/AKT/mTOR 通路抑制剂 LY294002 后，再次进行上述功能实验，以探讨其机制。最后，进行荷瘤小鼠的体内实验进行进一步验证。
结果
与非 TNBC 细胞系相比，TNBC 细胞的增殖、侵袭、迁移和肿瘤球形成能力以及血管生成能力显著增强。TNBC 组织和细胞中的 OPN 表达明显上调。OPN 的上调显著提高了细胞的增殖、侵袭和迁移能力以及肿瘤球形成和血管生成能力。其机制可能是通过激活 PI3K/AKT/mTOR 信号通路来调节谷胱甘肽过氧化物酶 4（GPX4）介导的抗脂质过氧化。
结论
OPN 通过激活 PI3K/AKT/mTOR 通路调节 GPX4 介导的抗脂质过氧化水平，促进 TNBC 中的肿瘤球形成和血管生成。
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