Oncogene activation in human benign tumors of the skin (keratoacanthomas): is HRAS involved in differentiation as well as proliferation?

Corominas, Montserrat; Kamino, Hideko; León, Javier; Pellicer, Ángel Antonio Blasco

doi:10.1073/pnas.86.16.6372

Cited by 82 publications

(45 citation statements)

References 36 publications

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“…This is in good agreement with the ®nding that also benign and malignant skin tumors (keratoacanthomas and squamous cell carcinomas) share some common genetic alterations and that e.g. ras H oncogene is among those common aberrations (Corominas et al, 1989).…”

Section: Discussionsupporting

confidence: 91%

Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature

et al. 1999

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UV-radiation is a major risk factor for non-melanoma skin cancer causing speci®c mutations in the p53 tumor suppressor gene and other genetic aberrations. We here propose that elevated temperature, as found in sunburn areas, may contribute to skin carcinogenesis as well. Continuous exposure of immortal human HaCaT skin keratinocytes (possessing UV-type p53 mutations) to 408C reproducibly resulted in tumorigenic conversion and tumorigenicity was stably maintained after recultivation of the tumors. Growth at 408C was correlated with the appearance of PARP, an enzyme activated by DNA strand breaks and the level corresponded to that seen after 5 Gy g-radiation. Concomitantly, comparative genomic hybridization (CGH) analyis demonstrated that chromosomal gains and losses were present in cells maintained at 408C while largely absent at 378C. Besides individual chromosomal aberrations, all tumor-derived cells showed gain of chromosomal material on 11q with the smallest common region being 11q13.2 to q14.1. Cyclin D1, a candidate gene of that region was overexpressed in all tumor-derived cells but cyclinD1/ cdk4/cdk6 kinase activity was not increased. Thus, these data demonstrate that long-term thermal stress is a potential carcinogenic factor in this relevant skin cancer model, mediating its e ect through induction of genetic instability which results in selection of tumorigenic cells characterized by gain of 11q.

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Section: Discussionsupporting

confidence: 91%

Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature

et al. 1999

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“…12 Tumor regression was also observed in Ha-ras oncogene-related human and rabbit keratoacanthomas. 5,10 The phenomenon of spontaneous regression is strong evidence for the involvement of both hair follicle influence and ras oncogenes in the early stages of keratinocyte neoplasia. Because the function of CRPV URR and EJras expression may be related to hair follicle activity during hair growth, it can be imagined that the regression may be related to discontinued expression of EJras because of the recession of the hair follicle activity.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is known that the incidences of both keratoacanthoma and SCC show parallel increases with increased sun exposure. 24 In correlation with this, a relatively high incidence of the mutated Ha-ras oncogene has been found in keratoacanthomas from both human and experimental models, 5,10 and in human and animal cutaneous SCC. 16,[25][26][27] These findings further suggest that ras oncogenes play important roles in all steps of tumor initiation, regression, and progression, and that additional cellular factors appear to be involved in the malignant progression.…”

mentioning

confidence: 95%

“…It was reported that 30% of human keratoacanthomas and 13% of squamous cell carcinomas (SCCs) contained specific mutations (A-to-T transversion) in codon 61 of the c-Ha-ras oncogene. 5 Another study reported that 40% of the human skin cancers studied contained mutations in codon 12 of Ha-ras. 6 These results clearly indicate the involvement of activated Ha-ras genes in the development of both benign and malignant skin tumors.…”

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confidence: 99%

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Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

Peng

Griffith

Han

et al. 1999

The American Journal of Pathology

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Activated ras genes have been frequently identified in both benign and malignant human tumors , including keratoacanthoma and squamous cell carcinoma. In this study , we developed two lines of transgenic rabbits in which the expression of EJras has been specifically targeted to the rabbit epidermal keratinocytes , using the upstream regulatory region of cottontail rabbit papillomavirus. All of the F1 transgenic progenies developed multiple keratoacanthomas at about 3 days after birth. The rabbits developed an average of 20 tumors , which usually reached the size of approximately 1 cm in diameter and then spontaneously regressed in about 2 months , similar to keratoacanthoma regression in humans. In addition , up to 18% of the rabbits then developed squamous cell carcinoma at about 5 months of age. The expression of EJras was detectable in all of the keratoacanthomas and squamous cell carcinomas. These results strongly support the involvement of the ras oncogene in both the initiation and regression of keratoacanthoma , and in the development of squamous cell carcinomas. These novel transgenic rabbits , with their consistent tumorigenic phenotype at an early age , high similarity to the human lesions, and easy accessibility for examination , manipulation, biopsy , and treatment , should provide a unique model system for studying ras activation-related tumor initiation , regression , and progression , and for evaluating antitumor therapies. (Am J Pathol 1999, 155:315-324)Ras genes encode a family of plasma membrane-bound proteins (p21ras) that function as intermediates in cell signal transduction pathways. These proteins play a pivotal role in regulating cell growth and differentiation in nearly all studied eukaryotic cell types. 1 The activity of ras proteins as regulating switches is strictly controlled by cycling between active GTP-bound and inactive GDPbound states. 2 The active and inactive cycling of the p21ras proteins may be broken because of a point mutation at position 12, 13, or 61 of the proteins, which has been found in both experimental and spontaneous tumors. This cellular transformation property is considered to be due to the extended life and resultant accumulation of p21ras proteins in the active GTP state, 3 which leads to tumorigenesis due to loss of regulatory control of cell proliferation and differentiation. However, many aspects of ras mutation-related neoplasia still remain to be elucidated, especially the dual roles of activated ras genes in cell growth stimulation or differentiation, and its correlation with tumor initiation, regression, and progression.It is well known that carcinogenesis is a complex multistep process that usually involves mutation and/or inappropriate expression of certain cellular genes, such as the mutational activation of proto-oncogenes and the inactivation of tumor suppressor genes. Among the oncogenes, activated ras genes have been found in a wide variety of human tumors, and ranges from 10 -20% Haras activation in bladder carcinomas to 85-100% Ki-ras in colorec...

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“…Prior to assaying for a ras mutation, the exon containing the possible ras mutation was amplified by the polymerase chain reaction (PCR) (8)(9)(10). In the first assay, the amplified samples were then affixed to nylon membranes using a slot blot apparatus, and the membranes were hybridized to 32P-labeled oligonucleotides specific for the relevant point mutations.…”

Section: Methods To Detect Ras Mutationsmentioning

confidence: 99%

ras activation in human tumors and in animal model systems.

Corominas

Sloan

León

et al. 1991

Environ Health Perspect

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Environmental agents such as radiation and chemicals are known to cause genetic damage. Alterations in a limited set of cellular genes called proto-oncogenes lead to unregulated proliferation and differentiation. We have studied the role of the ras gene family in carcinogenesis using two different animal models. In one case, thymic lymphomas were induced in mice by either gamma or neutron radiation, and in the other, keratoacanthomas were induced in rabbit skin with dimethylbezanthracene. Human keratoacanthomas similar to the ones induced in rabbits were also analyzed. We found that different types of radiation such as gamma rays and neutrons, induced different point mutations in ras genes. A novel Kras mutation in codon 146 has been found in thymic lymphomas induced by neutrons. Keratoacanthomas induced in rabbit skin by dimethylbenzanthracene show a high frequency of H-ras-activated genes carrying a mutation in codon 61. The same is observed in human keratoacanthomas, although mutations are in both the 12th and the 61st codons of the H-ras gene. H-ras activation is less frequent in human squamous cell carcinomas than in keratoacanthomas, suggesting that ras genes could play a role in vivo in differentiation as well as in proliferation.

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Oncogene activation in human benign tumors of the skin (keratoacanthomas): is HRAS involved in differentiation as well as proliferation?

Cited by 82 publications

References 36 publications

Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature

Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature

Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

ras activation in human tumors and in animal model systems.

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