文章：

外显子连接复合体组分 EIF4A3 在胰腺导管腺癌中具有与剪接相关的致癌作用

Caveolin-1 knockout mitigates breast cancer metastasis to the lungs via integrin α3 dysregulation in 4T1-induced syngeneic breast cancer model 

原文发布日期：2024-09-07 

英文摘要：

Caveolin-1 (Cav-1) is a critical lipid raft protein playing dual roles as both a tumor suppressor and promoter. While its role in tumorigenesis, progression, and metastasis has been recognized, the explicit contribution of Cav-1 to the onset of lung metastasis from primary breast malignancies remains unclear. Here, we present the first evidence that Cav-1 knockout in mammary epithelial cells significantly reduces lung metastasis in syngeneic breast cancer mouse models. In vitro, Cav-1 knockout in 4T1 cells suppressed extracellular vesicle secretion, cellular motility, and MMP secretion compared to controls. Complementing this, in vivo analyses demonstrated a marked reduction in lung metastatic foci in mice injected with Cav-1 knockout 4T1 cells as compared to wild-type cells, which was further corroborated by mRNA profiling of the primary tumor. We identified 21 epithelial cell migration genes exhibiting varied expression in tumors derived from Cav-1 knockout and wild-type 4T1 cells. Correlation analysis and immunoblotting further revealed that Cav-1 might regulate metastasis via integrin α3 (ITGα3). In silico protein docking predicted an interaction between Cav-1 and ITGα3, which was confirmed by co-immunoprecipitation. Furthermore, Cav-1 and ITGα3 knockdown corroborated its role in metastasis in the cell migration assay. 

摘要翻译：

Caveolin-1（Cav-1）是一种重要的脂筏蛋白，兼具肿瘤抑制因子和促进因子的双重功能。虽然其在肿瘤发生、进展和转移中的作用已被认可，但Cav-1对原发性乳腺癌肺转移发生的具体机制尚不明确。本研究首次发现：在同系乳腺癌小鼠模型中，乳腺上皮细胞Cav-1基因敲除可显著降低肺转移发生率。体外实验表明，与对照组相比，4T1细胞的Cav-1敲除抑制了细胞外囊泡分泌、细胞运动能力和MMP分泌。与之对应，体内实验显示注射Cav-1敲除4T1细胞的小鼠肺转移灶较野生型细胞组显著减少，该结果通过原发肿瘤mRNA谱分析得到进一步验证。我们鉴定出21个上皮细胞迁移相关基因在Cav-1敲除与野生型4T1细胞来源的肿瘤中呈现差异化表达。相关性分析和免疫印迹进一步揭示Cav-1可能通过整合素α3（ITGα3）调控转移过程。计算机蛋白质对接预测Cav-1与ITGα3存在相互作用，该预测通过免疫共沉淀实验得到证实。此外，在细胞迁移实验中，Cav-1与ITGα3的基因 knockdown 共同验证了其在转移过程中的作用。

原文链接：

Caveolin-1 knockout mitigates breast cancer metastasis to the lungs via integrin α3 dysregulation in 4T1-induced syngeneic breast cancer model