Abstract
Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathway. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer.
MeSH terms
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Aged
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Animals
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Apoptosis / drug effects
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Cell Differentiation
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Cell Line, Tumor
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Cell Movement
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Cell Proliferation
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Down-Regulation
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ErbB Receptors / metabolism*
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Erlotinib Hydrochloride
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Female
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Gene Knockdown Techniques
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Humans
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Ki-67 Antigen / analysis
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Male
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Mice
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Mice, Nude
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Middle Aged
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Pancreatic Neoplasms / chemistry
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / metabolism*
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Prognosis
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Quinazolines / pharmacology
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Quinazolines / therapeutic use
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Signal Transduction
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Survival Rate
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Tumor Suppressor Proteins / analysis
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Tumor Suppressor Proteins / therapeutic use
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Ubiquitin-Protein Ligases / analysis
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitin-Protein Ligases / therapeutic use
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Ubiquitination*
Substances
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Ki-67 Antigen
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Protein Kinase Inhibitors
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Quinazolines
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Tumor Suppressor Proteins
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Erlotinib Hydrochloride
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STUB1 protein, human
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Ubiquitin-Protein Ligases
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EGFR protein, human
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ErbB Receptors