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Oncogene involvement in tumor regression: H-ras activation in the rabbit keratoacanthoma model
M Corominas1, J Leon, H Kamino
1Department of Pathology, New York University Medical Center, New York 10016.
Abstract:
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.
Insights
Activated H-ras genes are involved in skin tumor development. In keratoacanthomas, H-ras activation may promote regression, not malignancy, suggesting other oncogenes drive cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Carcinogenesis
Background:
- Ras oncogenes play a role in tumorigenesis.
- 7,12-dimethylbenz(a)anthracene (DMBA) induces skin tumors in rabbits.
- Keratoacanthomas are benign, self-regressing tumors, while squamous cell carcinomas are malignant.
Purpose of the Study:
- Investigate the involvement of ras oncogenes in the development of keratoacanthomas and squamous cell carcinomas.
- Determine the specific mutations and expression levels of the H-ras gene in these tumors.
- Understand the role of H-ras activation in tumor progression and regression.
Main Methods:
- Induction of tumors in rabbit ears using DMBA.
- Cloning and sequencing of the rabbit H-ras gene.
- Polymerase Chain Reaction (PCR) analysis to detect mutations in H-ras codons 12 and 61.
- Analysis of H-ras transcript levels.
Main Results:
- Approximately 82% of keratoacanthomas showed an A:T to T:A transversion in H-ras codon 61.
- Increased H-ras transcript levels were observed in keratoacanthomas compared to normal skin.
- Squamous cell carcinomas exhibited a lower frequency (40%) of H-ras codon 61 activation, with some showing H-ras codon 12 mutations or N-ras activation.
Conclusions:
- DMBA induces distinct genetic lesions, including H-ras activation in keratoacanthomas and potentially other oncogene activations in squamous cell carcinomas.
- H-ras gene activation alone is insufficient for malignant transformation or sustained benign tumor growth.
- Activated H-ras may play a role in the regression of benign skin tumors.