CEMIP upregulates BiP to promote breast cancer cell survival in hypoxia.
CEMIP upregulates BiP to promote breast cancer cell survival in hypoxia.
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DOI：
10.18632/oncotarget.27036
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发表时间：
2019-07-02
期刊：
影响因子：
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通讯作者：
Lin, Richard Z
中科院分区：
文献类型：
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作者：
Banach, Anna;Jiang, Ya-Ping;Lin, Richard Z
细胞迁移诱导蛋白（CEMIP）和结合免疫球蛋白（BiP）在人类癌症中表达上调，促进癌症进展和转移。研究表明，CEMIP 存在于内质网 (ER) 中，与 BiP 相互作用以诱导细胞迁移，但这两种蛋白质之间的关系此前尚不清楚。在这里，我们证明 CEMIP 介导 BiP 启动子的激活并上调乳腺癌细胞系中 BiP 转录物和蛋白质水平。此外，CEMIP 过表达通过减少细胞凋亡、激活自噬和增加葡萄糖摄取，在缺氧条件下赋予癌细胞保护性适应，从而促进肿瘤生长。我们证明 BiP 在 CEMIP 下游发出信号，调节细胞对缺氧的抵抗力。减少表达 CEMIP 的细胞中的 BiP 可使细胞对缺氧治疗敏感，减少葡萄糖摄取，并导致体内肿瘤消退。我们的研究深入了解了 CEMIP 和 BiP 表达之间的联系以及它们在缺氧中发挥的促生存作用。更好地了解癌细胞适应恶劣肿瘤环境的机制可能会导致改进癌症治疗的发展。
Cell migration-inducing protein (CEMIP) and binding immunoglobulin protein (BiP) are upregulated in human cancers, where they drive cancer progression and metastasis. It has been shown that CEMIP resides in the endoplasmic reticulum (ER) where it interacts with BiP to induce cell migration, but the relationship between the two proteins was previously unknown. Here we show that CEMIP mediates activation of the BiP promoter and upregulates BiP transcript and protein levels in breast cancer cell lines. Moreover, CEMIP overexpression confers protective adaptations to cancer cells under hypoxic conditions, by decreasing apoptosis, activating autophagy, and increasing glucose uptake, to facilitate tumor growth. We demonstrate that BiP signals downstream of CEMIP, modulating cellular resistance to hypoxia. Reducing BiP in CEMIP-expressing cells sensitized cells to hypoxia treatment, decreased glucose uptake, and resulted in tumor regression in vivo. Our study provides insights into the link between CEMIP and BiP expression and the pro-survival role they play in hypoxia. Better understanding of the mechanisms behind cancer cell adaptations to harsh tumor environments could lead to development of improved cancer treatments.