MIIP accelerates epidermal growth factor receptor protein turnover and attenuates proliferation in non-small cell lung cancer
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Jing Wen1,2, Jianhua Fu2,3, Yihong Ling2,4 and Wei Zhang1
1 Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2 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
3 Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China
4 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China
Wei Zhang, email:
Keywords: migration and invasion inhibitory protein, epidermal growth factor receptor, protein degradation, non-small cell lung cancer
Received: September 27, 2015 Accepted: January 17, 2016 Published: January 26, 2016
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.
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