Abstract
Epidermal growth factor receptor (EGFR) is frequently aberrantly expressed in cancer, and abnormal signalling downstream of this receptor contributes to tumour growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. Aberrant signalling downstream of this receptor contributes to tumour invasion. We previously reported that EGFRvIII can promote hepatocellular carcinoma (HCC) invasion. However, little is known concerning the mechanisms underlying EGFRvIII-mediated increases in cell motility and invasion in HCC. In this study, we observed that S100A11 was significantly upregulated in Huh-7 cells that overexpressed EGFRvIII. Moreover, S100A11 expression was elevated in HCC tissue samples (68.6%; 35/51), and this elevation was correlated with EGFRvIII expression (p = 0.0020; n = 20). Furthermore, the overexpression of S100A11 can promote HCC cell invasiveness, whereas siRNA against S100A11 can suppress the invasiveness of HCC cells stably transfected with EGFRvIII. Additionally, STAT3 inhibitors can block S100A11 expression and S100A11 promoter activity in HCC cells with stable overexpression of EGFRvIII. Furthermore, mutation in STATx binding sites could abolish the S1000A11 promoter activity stimulation by EGFRvIII. Taken together, the results demonstrate that the EGFRvIII-STAT3 pathway promotes cell migration and invasion by upregulating S100A11.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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ErbB Receptors / genetics*
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ErbB Receptors / metabolism
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Gene Expression Regulation, Neoplastic*
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Humans
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Liver Neoplasms / genetics*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Mutation
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Neoplasm Invasiveness
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Promoter Regions, Genetic
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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S100 Proteins / antagonists & inhibitors
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S100 Proteins / genetics*
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S100 Proteins / metabolism
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics*
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Tyrphostins / pharmacology
Substances
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RNA, Small Interfering
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S100 Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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epidermal growth factor receptor VIII
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S100A11 protein, human
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ErbB Receptors
Grants and funding
This work was supported by the Key Program of the Shanghai Science and Technology Committee (No. 10431903700), the Supporting Program of the “Twelfth Five-Year Plan” for Science & Technology Research of China (2012ZX10002015-007), the National Natural Science Foundation of China (No. 81071746), and the research fund of the State Key Laboratory of Oncogenes and Related Genes (91-11-03/05). This work was supported by the Key Program of the Shanghai Science and Technology Committee (No. 10431903700), the Supporting Program of the “Twelfth Five-Year Plan” for Science & Technology Research of China (2012ZX10002015-007), the National Natural Science Foundation of China (No. 81071746), and the research fund of the State Key Laboratory of Oncogenes and Related Genes (91-11-03/05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.