EGFR expression is linked to osteopontin and Nf-κB signaling in clear cell renal cell carcinoma
- 413 Downloads
Aim and background
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in many important aspects of cell biology that are related to tumorigenesis. There are opposite evidences of the role of EGFR in renal cancer and the outcome of EGFR-targeted therapies, suggesting the complexity of EGFR signaling pathways. In vitro, osteopontin (OPN) and nuclear factor kappa B (NF-κB) are thought to be involved in specific ligand-independent EGFR activation that could have a role in resistance to EGFR mAb therapy. Aim of this study was to analyze the relationship between EGFR and OPN at the protein and mRNA level, as well as their relation to NF-κB in clear cell renal cell carcinoma (CCRCC).
Materials and methods
Expression of EGFR, OPN, and p65 NF-κB protein was analyzed using immunohistochemistry and compared mutually in 88 CCRCC samples. Expression of EGFR and OPN mRNAs was analyzed using quantitative Real-time PCR in 22 CCRCC samples and compared mutually and with NF-κB protein expression.
Epidermal growth factor receptor mRNA level was higher in CCRCC samples in comparison with normal renal tissue (p = 0.012) and was associated with high OPN mRNA level, and with NF-κB activation (p < 0.001 and p = 0.045, respectively). Immunohistochemical staining showed the inverse association; high EGFR protein expression was related with low OPN and NF-κB protein expression (p < 0.001 and p = 0.047, respectively).
Epidermal growth factor receptor gene is upregulated in CRCC and associated with OPN gene expression and NF-kB signaling. The inverse relation between OPN and EGFR at the protein level could probably reflect dynamic changes that EGFR undergoes following activation.
KeywordsRenal cell carcinoma EGFR Nuclear factor kappa B Osteopontin Tissue array analysis
This work was supported by the Ministry of Science, Education, and Sports of the Republic of Croatia (grant 062-0620095-0078), Alpe-Adria Research Grant and MIUR grant, Italy and TransMedRi GA No. 256686. We thank Mrs. Tanja Kovačević and Mr. Ozren Štanfel for their excellent technical support.
Conflict of interest
- 17.Matušan-Ilijaš K, Damante G, Fabbro D, Đorđević G, Hadžisejdić I, Grahovac M, Marić I, Španjol J, Grahovac B, Jonjić N, Lučin K (2011) Osteopontin expression correlates with nuclear factor-kappa B activation and apoptosis downregulation in clear cell renal cell carcinoma. Pathol Res Pract 207:104–110PubMedCrossRefGoogle Scholar
- 21.Chakalaparampil I, Peri A, Nemir M, Mckee MD, Lin PH, Mukherjee BB, Mukherjee AB (1996) Cells in vivo and in vitro from osteopetrotic mice homozygous for c-src disruption show suppression of synthesis of osteopontin, a multifunctional extracellular matrix protein. Oncogene 12:1457–1467Google Scholar
- 27.Merseburger AS, Hennenlotter J, Simon P, Kruck S, Koch E, Horstmann M, Kuehs U, Küfer R, Stenzl A, Kuczyk MA (2005) Membranous expression and prognostic implications of epidermal growth factor receptor protein in human renal cell cancer. Anticancer Res 3:1901–1907Google Scholar
- 32.Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D (2007) Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 25(29):4536–4541PubMedCrossRefGoogle Scholar
- 33.Jermann M, Stahel RA, Salzberg M, Cerny T, Joerger M, Gillessen S, Morant R, Egli F, Rhyner K, Bauer JA, Pless M (2006) A phase II, open-label study of gefitinib (IRESSA) in patients with locally advanced, metastatic, or relapsed renal-cell carcinoma. Cancer Chemother Pharmacol 57:533–539PubMedCrossRefGoogle Scholar
- 35.Ravaud A, Hawkins R, Gardner JP, von der Maase H, Zantl N, Harper P, Rolland F, Audhuy B, Machiels JP, Pétavy F, Gore M, Schöffski P, El-Hariry I (2008) Lapatinib versus hormone therapy in patients with advanced renal cell carcinoma: a randomized phase III clinical trial. J Clin Oncol 26:2285–2291PubMedCrossRefGoogle Scholar