Oncogene involvement in tumor regression: H-ras activation in the rabbit keratoacanthoma model.
Activated H-ras genes are present in a number of skin tumors induced in animals by carcinogen treatment. The involvement of the ras oncogenes in tumorigenesis was investigated in keratoacanthomas, benign and self-regressing tumors, as well as malignant squamous cell carcinomas. Both tumors were induced in rabbit ears by repeated applications of 7,12 dimethylbenz(a)anthracene (DMBA). The rabbit H-ras gene was cloned and sequenced. PCR analysis revealed that approximately 82% of the keratoacanthoma DNAs contained an A:T to T:A transversion in codon 61. The relative levels of H-ras transcript were increased in keratoacanthomas compared to normal skin and the activated allele was expressed in tumors, even during the regressing phase. Although a G:C to A:T mutation in codon 12 of the H-ras and an activated N-ras gene were found in two squamous cell carcinomas, the frequency of H-ras activation in codon 61 was much lower (40%) in the malignant tumours induced by the same carcinogen treatment. Therefore, DMBA induced at least two types of genetic lesions in this system: H-ras activation, present in most regressing keratoacanthomas, and activation of other unidentified oncogenes which may result in the development of malignant tumors. Our observations indicate that expression of an activated H-ras gene, in this system, is neither sufficient to induce a malignant phenotype nor even capable of maintaining the growth of a benign tumor and suggest that it could be involved in tumor regression.
Corominas
M
M
Department of Pathology, New York University Medical Center, New York 10016.
Leon
J
J
Kamino
H
H
Cruz-Alvarez
M
M
Novick
S C
SC
Pellicer
A
A
D015127:9,10-Dimethyl-1,2-benzanthracene; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics; D003001:Cloning, Molecular; D004247:DNA / Q000032:analysis / Q000302:isolation & purification; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000187:drug effects; D007636:Keratoacanthoma / Q000139:chemically induced / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009365:Neoplasm Regression, Spontaneous / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D012689:Sequence Homology, Nucleic Acid; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*
D012333:RNA, Messenger; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA