We have determined the prevalence of amplification of c‐myc, N‐myc, L‐myc, H‐ras, Ki‐ras, and N‐ras oncogenes in 23 cases of squamous cell carcinoma of the oral cavity, using Southern hybridization analysis of DNA extracted from the primary tumor tissues. Nick‐translated oncogene probes and oncogene inserts labeled to high specific activities were used. We observed a 5‐ to 10‐fold amplification of one or more of c‐myc, N‐myc, Ki‐ras and N‐ras oncogenes in 56% of the tumor tissue samples, with these oncogenes not being amplified in the peripheral blood cells of the same patients, L‐myc and H‐ras were not amplified in any of our samples. The oncogene amplifications seemed to be associated with advanced stages of squamous cell carcinomas, with the ras and myc family oncogenes being amplified in stages 3 and 4. Hybridization with N‐myc detected an additional 2.3 kb EcoRI fragment, along with the normal 2.1 kb fragment. Our data also demonstrated amplification of multiple oncogenes in the same tumor tissue sample. About 60% of the samples with amplified oncogenes showed simultaneous amplification of 2 or more oncogenes. The results showing different oncogene amplifications in similar tumors, as well as multiple oncogene amplifications in the same tumor, suggest that these oncogenes may be alternatively or simultaneously activated in oral carcinogenesis.
Enhancing factor (EF), a growth regulatory molecule, isolated from mouse small intestines, has been well characterized in this laboratory. It increases the binding of epidermal growth factor in a unique manner via its own receptor. In the first 20 N-terminal amino acids sequenced, EF showed 50% homology to human Group II phospholipase A2 (PLA2). Here we propose that EF is yet another, unidentified isoform of PLA2 which regulates cell proliferation via modulation of EGF binding. To our knowledge, this is the first report implicating PLA2-II-like molecules in growth regulation.
In this study the nature of binding of enhancing factor (EF) and its mode of action are examined. EF binds to A431 cells through its own receptor, which is distinct from the receptor for epidermal growth factor (EGF). EF binds to the cell membrane and in turn provides a binding site for EGF. Data analyzed from Scatchard plots show that prior treatment of formalin-fixed A431 cells with EF for 30 minutes results in an increase in the number of binding sites for 125I-EGF. 3H-Thymidine incorporation studies, using the EGF-receptorless cell line NR-6, indicate that neither EF nor EGF alone stimulates the cells to synthesise DNA, but when both are added together the cells show 3H-thymidine incorporation. The role of EF may be to trap EGF and make it available to the cells through its own receptors even in the absence of EGF receptors. EF also induces anchorage-independent growth of normal fibroblasts in soft agar only in the presence of EGF.
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