K-Ras gene status and expression of Ras/mitogen-activated protein kinase (MAPK) signaling molecules in ameloblastomas.
BACKGROUND
To clarify the roles of rat sarcoma (Ras)/mitogen-activated protein kinase (MAPK) signaling pathway in oncogenesis and cytodifferentiation of odontogenic tumors, K-Ras gene status and expression of Ras, Raf1, MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)1, and ERK1/2 proteins were analyzed in ameloblastomas as well as in tooth germs.


METHODS
Paraffin sections of 10 tooth germs and 46 benign and 6 malignant ameloblastomas were examined immunohistochemically for the expression of K-Ras, Raf1, MEK1, and ERK1/2. Frozen tissue samples of 22 benign ameloblastomas and 1 malignant (metastasizing) ameloblastoma were analyzed by direct DNA sequencing to detect K-Ras gene alteration.


RESULTS
Immunohistochemical reactivity for K-Ras, Raf1, MEK1, and ERK1/2 was detected in both normal and neoplastic odontogenic epithelium, and these molecules were reactive chiefly with odontogenic epithelial cells neighboring the basement membrane. Plexiform ameloblastomas showed slightly stronger expression of these Ras/MAPK signaling molecules than follicular ameloblastomas. Keratinizing cells and granular cells showed decreased reactivity for the signaling molecules. Basal cell ameloblastomas showed slightly stronger reactivity for the signaling molecules than did the other subtypes. K-Ras immunoreactivity in malignant ameloblastomas was lower than that in dental lamina of tooth germs. Direct DNA sequencing showed a GGT to GCT point mutation at codon 12 of K-Ras gene in one ameloblastoma.


CONCLUSIONS
Expression of K-Ras, Raf1, MEK1, and ERK1/2 in tooth germs and ameloblastomas suggests that Ras/MAPK signaling pathway functions to regulate cell proliferation and differentiation in both normal and neoplastic odontogenic epithelium. K-Ras gene status implied that K-Ras mutations might play a minor role in oncogenesis of odontogenic epithelium.
Kumamoto
Hiroyuki
H
Division of Oral Pathology, Department of Oral Medicine and Surgery, Tohoku University Gradudate School of Dentistry, Sendai, Japan. kumamoto@mail.tains.tohoku.ac.jp
Takahashi
Nobuhiro
N
Ooya
Kiyoshi
K
D000564:Ameloblastoma / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D048049:Extracellular Signal-Regulated MAP Kinases; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007573:Jaw Neoplasms / Q000201:enzymology / Q000235:genetics*; D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D017354:Point Mutation; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis; D014083:Tooth Germ / Q000201:enzymology; D018631:ras Proteins / Q000096:biosynthesis
D009363:Neoplasm Proteins; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C089319:Ras-dependent mitogen-activated protein kinase kinase kinase; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins