Abstract
In order to model squamous cell carcinoma development in vivo, researchers have long preferred hairless mouse models such as SKH-1 mice that have traditionally been classified as ‘wild-type’ mice irrespective of the genetic factors underlying their hairless phenotype. The work presented here shows that mutations in the Hairless (Hr) gene not only result in the hairless phenotype of the SKH-1 and Hr−/− mouse lines but also cause aberrant activation of NFκB and its downstream effectors. We show that in the epidermis, Hr is an early UVB response gene that regulates NFκB activation and thereby controls cellular responses to irradiation. Therefore, when Hr expression is decreased in Hr mutant animals there is a corresponding increase in NFκB activity that is augmented by UVB irradiation. This constitutive activation of NFκB in the Hr mutant epidermis leads to the stimulation a large variety of downstream effectors including the cell cycle regulators cyclin D1 and cyclin E, the anti-apoptosis protein Bcl-2, and the pro-inflammatory protein Cox-2. Therefore, Hr loss results in a state of uncontrolled epidermal proliferation that promotes tumor development, and Hr mutant mice should no longer be considered merely hairless 'wild-type' mice. Instead, Hr is a crucial UVB response gene and its loss creates a permissive environment that potentiates increased tumorigenesis.
Highlights
As a group, non-melanoma skin cancers (NMSC) are the most common type of cancer in the US with a combined incidence of over 2 million new cases annually [1]
Hr increases susceptibility to UVB induced tumorigenesis In order to place our studies in the context of earlier work, we first confirmed that the mouse lines SKH-1 and Hrhr both contained the mutation, a proviral insertion disrupting the open reading frame of Hr (Figure S1)
The animals given only tap water developed signs of aggressive Squamous cell carcinoma (SCC) (Figure S3A). These results demonstrate that the tumor susceptibility of the SKH-1 animals is dependent on the overactivation of the NFkB pathway that is a downstream result of Hairless mutation
Summary
Non-melanoma skin cancers (NMSC) are the most common type of cancer in the US with a combined incidence of over 2 million new cases annually [1]. Current research strategies utilize mice strains that lack hair to model carcinogenesis using either UV irradiation or chemical carcinogenesis since researchers prefer not to perform repeated shaving or depilation to visualize tumor development. Favored strains feature mutations in the Hairless (Hr) gene (Entrez Gene ID 15460) that result in almost complete hair loss early in life [6]. Hr mutant mice were widely adopted as a convenient model for skin carcinogenesis studies and were discovered to be uniquely susceptible to both UV induced and chemical carcinogenesis [10,11,12]. Despite the knowledge that these strains have a mutated Hr gene, many carcinogenesis studies continue to use them and refer to unirradiated/untreated animals as ’wild-type hairless’ mice
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