MIIP accelerates epidermal growth factor receptor protein turnover and attenuates proliferation in non-small cell lung cancer.
MIIP accelerates epidermal growth factor receptor protein turnover and attenuates proliferation in non-small cell lung cancer.
复制标题
MIIP 加速表皮生长因子受体蛋白周转并减弱非小细胞肺癌的增殖
DOI：
10.18632/oncotarget.7001
复制
发表时间：
2016-02-23
期刊：
影响因子：
--
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Wen J;Fu J;Ling Y;Zhang W
迁移和侵袭抑制蛋白（Migration and Invasion Inhibitory Protein，MIIP）是近年来发现的一种具有抑制细胞增殖和迁移功能的蛋白质。与对照细胞相比，MIIP过表达降低了肺癌细胞中表皮生长因子受体（EGFR）蛋白的细胞内稳态水平，而对EGFR mRNA表达无影响。这种MIIP促进的EGFR蛋白降解被蛋白酶体和溶酶体抑制剂逆转，表明蛋白酶体和溶酶体途径参与了这种降解。这一发现进一步验证了脉冲追踪实验使用35 S-蛋氨酸代谢标记。我们发现MIIP通过内质网中的蛋白酶体降解加速EGFR蛋白周转，然后在其进入胞吞运输后通过溶酶体途径加速EGFR蛋白周转。MIIP刺激的EGFR下调抑制Ras的下游活化并阻断MEK信号转导途径，导致细胞增殖抑制。在肺腺癌样品中验证了MIIP和EGFR蛋白表达之间的负相关性。此外，较高的MIIP蛋白表达预测接受根治性手术的IA-IIIA期肺腺癌患者的总生存率更高。这些发现揭示了MIIP抑制细胞增殖的新机制。
The migration and invasion inhibitory protein (MIIP) has been discovered recently to have inhibitory functions in cell proliferation and migration. Overexpression of MIIP reduced the intracellular steady-state level of epidermal growth factor receptor (EGFR) protein in lung cancer cells with no effect on EGFR mRNA expression compared to that in the control cells. This MIIP-promoted EGFR protein degradation was reversed by proteasome and lysosome inhibitors, suggesting the involvement of both proteasomal and lysosomal pathways in this degradation. This finding was further validated by pulse-chase experiments using 35S-methionine metabolic labeling. We found that MIIP accelerates EGFR protein turnover via proteasomal degradation in the endoplasmic reticulum and then via the lysosomal pathway after its entry into endocytic trafficking. MIIP-stimulated downregulation of EGFR inhibits downstream activation of Ras and blocks the MEK signal transduction pathway, resulting in inhibition of cell proliferation. The negative correlation between MIIP and EGFR protein expression was validated in lung adenocarcinoma samples. Furthermore, the higher MIIP protein expression predicts a better overall survival of Stage IA-IIIA lung adenocarcinoma patients who underwent radical surgery. These findings reveal a new mechanism by which MIIP inhibits cell proliferation.