Mesothelin promotes anchorage-independent growth and prevents anoikis via extracellular signal-regulated kinase signaling pathway in human breast cancer cells
Mesothelin promotes anchorage-independent growth and prevents anoikis via extracellular signal-regulated kinase signaling pathway in human breast cancer cells
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DOI：
10.1158/1541-7786.mcr-07-0254
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发表时间：
2008-02-01
影响因子：
5.2
通讯作者：
Tsubura, Airo
中科院分区：
文献类型：
--
作者：
Uehara, Norihisa;Matsuoka, Yoichiro;Tsubura, Airo
间皮素 (MSLN) 是一种在多种肿瘤中过度表达的糖蛋白。 MSLN 存在于细胞表面，也从 MSLN 阳性肿瘤细胞释放到体液或培养上清液中。尽管对 MSLN 作为诊断标记物或免疫治疗靶点进行了深入研究，但其生物学功能在很大程度上尚不清楚。在本研究中，我们检查了 MSLN 异位表达对人乳腺癌细胞系（MCF-7、T47D 和 MDA-MB-231）的影响。我们发现 MSLN 的过度表达促进了软琼脂中不依赖贴壁的生长。此外，表达高水平 MSLN 的 MDA-MB-231 细胞表现出对失巢凋亡（一种由脱离基质诱导的细胞凋亡）的抵抗性，DNA 碎片减少和促凋亡蛋白 Bim 下调表明了这一点。在 U0126（一种有丝分裂原激活蛋白/细胞外信号调节激酶激酶抑制剂）存在下孵育表达 MSLN 的 MDA-MB-231 细胞，可诱导 Bim 积累并恢复对失巢凋亡的敏感性。 Western blot 分析还表明，MSLN 的过度表达导致细胞外信号调节激酶 1/2 的持续激活和 Bim 的抑制。目前的结果构成了新的证据，表明 MSLN 通过细胞外信号调节激酶信号通路抑制 Bim 诱导，使细胞能够在不依赖贴壁的条件下生存。
Mesothelin (MSLN) is a glycoprotein that is overexpressed in various tumors. MSLN is present on the cell surface and is also released into body fluids or culture supernatants from MSLN-positive tumor cells. Despite intensive study of MSLN as a diagnostic marker or target for immunotherapy, its biological function is largely unknown. In the present study, we examined the effects of ectopic expression of MSLN in human breast cancer cell lines (MCF-7, T47D, and MDA-MB-231). We found that overexpression of MSLN promoted anchorage-independent growth in soft agar. In addition, MDA-MB-231 cells expressing high levels of MSLN exhibited resistance to anoikis (a type of apoptosis induced by detachment from substratum), as indicated by decreased DNA fragmentation and down-regulation of the proapoptotic protein Bim. Incubating MSLN-expressing MDA-MB-231 cells in the presence of U0126, an inhibitor of mitogen-activated protein/extracellular-signal-regulated kinase kinase, induced accumulation of Bim and restored susceptibility to anoikis. Western blot analysis also revealed that overexpression of MSLN resulted in sustained activation of extracellular signal-regulated kinase 1/2 and suppression of Bim. The present results constitute novel evidence that MSLN enables cells to survive under anchorage-independent conditions by suppressing Bim induction via the extracellular signal-regulated kinase signaling pathway.