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BCR:科学家揭开有益胆固醇双刃剑的神秘面纱

来源:生物谷 2013-10-11 00:26

2013年10月11日 讯 /生物谷BIOON/ --高水平的高密度脂蛋白(HDL)被认为是“有益胆固醇”,其可以保护机体抵御心脏疾病;然而其或许对机体其它方面具有不好的影响,来自托马斯杰斐逊大学的研究者表示,高水平的HDL或可以增加个体乳腺癌的风险,而且动物实验表明,其也可以增强癌症的侵袭性,该项研究成果刊登于国际杂志Breast Cancer Research上。

研究者Frank表示,如果我们可以阻断乳腺癌细胞中的HDL受体的活性,那么我们就可以在控制其对血管有益作用的同时而限制HDL对人体的有害作用;实验中,研究者将乳腺癌细胞系暴露于HDL中,结果发现乳腺癌发展过程中所涉及的信号通路被激活了,而且在模拟癌症转移的实验模型中发现细胞开始发生了迁移。

随后研究者使用沉默RNA限制了HDL受体SR-BI的表达从而减少了受体的水平,结果显示,促进肿瘤恶化的信号通路活性也随之降低了,另外携带有少量SR-BI受体的细胞也表现出较低的增殖比率,而且其相比正常SR-BI水平的细胞的迁移能力发生了降低。更为重要的是,水平减少的SR-BI和小鼠模型中肿瘤形成的降低直接相关。

研究者使用一种名为BLT-1的药物在乳腺癌细胞系中阻断了SR-BI的受体,结果发现和肿瘤形成相关的蛋白的信号和产生的速度明显降低了。这项研究肯定了HDL在恶性乳腺癌发展过程中的作用,而且通过抑制SR-BI的作用可以阻断癌症的发展。

未来研究者需要开发出更多的抑制SR-BI的药物,他们希望深入的研究将帮助其开发以SR-BI为靶点的药物,最终抑制肿瘤的发展。(生物谷Bioon.com)

Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development

Christiane Danilo, Jorge L Gutierrez-Pajares, Maria Antonietta Mainieri, Isabelle Mercier, Michael P Lisanti and Philippe G Frank

Introduction Previous studies have identified cholesterol as an important regulator of breast cancer development. High-density lipoprotein (HDL) and its cellular receptor, scavenger receptor class B type I (SR-BI) have both been implicated in the regulation of cellular cholesterol homeostasis, but their functions in cancer remain to be established. Methods In the present study, we have examined the role of HDL and SR-BI in the regulation of cellular signaling pathways in breast cancer cell lines and in the development of tumor in a mouse xenograft model. Results Our data show that HDL is capable of stimulating migration and can activate signal transduction pathways in the two human breast cancer cell lines, MDA-MB-231 and MCF7. Furthermore, we also show that knockdown of the HDL receptor, SR-BI, attenuates HDL-induced activation of the Phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (Akt) pathway in both cell lines. Additional investigations show that inhibition of the PI3K pathway, but not that of the mitogen-activated protein kinase (MAPK) pathway, could lead to a reduction in cellular proliferation in the absence of SR-BI. Importantly, while the knockdown of SR-BI led to decreased proliferation and migration in vitro, it also led to a significant reduction in tumor growth in vivo. Most importantly, we also show that pharmacological inhibition of SR-BI can attenuate signaling and lead to decreased cellular proliferation in vitro. Taken together, our data indicate that both cholesteryl ester entry via HDL-SR-BI and Akt signaling play an essential role in the regulation of cellular proliferation and migration, and, eventually, tumor growth. Conclusions These results identify SR-BI as a potential target for the treatment of breast cancer.

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