Expression of KIT, EGFR, HER-2 and tyrosine phosphorylation in undifferentiated thyroid carcinoma: implication for a new therapeutic approach.
The KIT, epidermal growth factor receptor (EGFR) and HER-2 oncoproteins have tyrosine kinase activity and are molecular targets in human cancer therapy. To clarify the significance of KIT, EGFR, and HER-2 in undifferentiated thyroid carcinoma (UTC), the expression of these receptors and tyrosine phosphorylation was examined immunohistochemically in resected cases of UTC and papillary thyroid carcinoma (PTC). KIT, EGFR, and HER-2 were also examined at the protein and mRNA levels in five UTC cell lines. KIT expression (1+), EGFR overexpression (2+/3+), HER-2 expression (1+), and tyrosine phosphorylation were detected immunohistochemically in 40%, 70%, 10%, and 50% of the 10 UTC. In 20 PTC, KIT, EGFR, and HER-2 were not detected, but tyrosine phosphorylation was detected in 25% of cases. In the five UTC cell lines, KIT expression (1+), EGFR overexpression (3+), HER-2 expression (1+), and tyrosine phosphorylation were detected immunocytochemically in 60%, 100%, 20%, and 40%, respectively. Western blot analysis did not detect KIT expression, but did detect EGFR and HER-2 expression in all five cell lines. Real-time polymerase chain reaction detected KIT mRNA in two of the cell lines (40%), EGFR in five (100%), and HER-2 in three (60%). The present findings suggest that EGFR overexpression was involved in the proliferation and development of UTC and was frequently accompanied by tyrosine phosphorylation. Expression of KIT and HER-2 appeared to be weak but significant, suggesting a possible role in the development of UTC. Molecular therapies targeting KIT, EGFR, HER-2, and/or tyrosine phosphorylation might be indicated for UTC.
Murakawa
Tetsuya
T
Department of Pathology II, National Defense Medical College and Hospital, Tokorozawa, Japan.
Tsuda
Hitoshi
H
Tanimoto
Takao
T
Tanabe
Tetsuya
T
Kitahara
Satoshi
S
Matsubara
Osamu
O
D000951:Antigens, Neoplasm / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism*
D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D019394:Ki-67 Antigen; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine