Wen Jing, Fu Jianhua, Ling Yihong, Zhang Wei
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China.
Oncotarget. 2016 Feb 23;7(8):9118-34. doi: 10.18632/oncotarget.7001.
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.
迁移和侵袭抑制蛋白（MIIP）最近被发现具有抑制细胞增殖和迁移的功能。与对照细胞相比，MIIP的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表达没有影响。蛋白酶体和溶酶体抑制剂可逆转这种MIIP促进的EGFR蛋白降解，表明蛋白酶体和溶酶体途径均参与了这种降解过程。使用35S-甲硫氨酸代谢标记的脉冲追踪实验进一步验证了这一发现。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，然后在其进入内吞运输后通过溶酶体途径加速周转。MIIP刺激的EGFR下调抑制了Ras的下游激活并阻断了MEK信号转导途径，从而导致细胞增殖受到抑制。在肺腺癌样本中验证了MIIP与EGFR蛋白表达之间的负相关。此外，较高的MIIP蛋白表达预示着接受根治性手术的IA-IIIA期肺腺癌患者的总体生存率更高。这些发现揭示了MIIP抑制细胞增殖的新机制。
