Conversion of C57Bl/6 mice from a tumor promotion-resistant to a -sensitive phenotype by enhanced ornithine decarboxylase expression

Abstract

A transgenic mouse model was developed in which ornithine decarboxylase (ODC) can be overexpressed in a tissue-specific and regulated manner. Hair follicle keratinocytes were targeted by use of a bovine keratin 6 (K6) promoter/regulatory region, and regulation was accomplished by using the tetracycline-regulated transactivator/tetracycline-response element system. Double-transgenic mice carrying both transgenes (K6/tetracycline-regulatable transactivator protein (tTA) and tetracycline-response element/Odc) on a C57Bl/6 background had no obvious phenotypic abnormalities in the absence (Odc transgene-expressed) of doxycycline (a tetracycline analog) in the drinking water. However, induction of K6-driven tTA expression by the tumor promoter (12-O-tetradecanoylphorbol-13-acetate) (TPA) led to very high levels of epidermal ODC activity and robust hyperplasia, especially involving hair follicles. Both effects were abolished by inclusion of doxycycline in the drinking water to repress transgene expression. Finally, the number of papillomas that developed in a standard (7,12-dimethybenz[a]anthracene) (DMBA)/TPA protocol was greatly reduced in mice in which transgenic Odc expression was repressed by doxycycline. Our results demonstrated that the higher levels of ODC expression produced in the transgenic model in the induced versus the repressed condition make the normally promotion-resistant C57Bl/6 strain much more sensitive to the short-term and long-term (i.e., tumor-promoting) effects of TPA.

Core promoter involvement in the induction of rat ornithine decarboxylase by phorbol esters

“…In mouse skin, overexpression of ODC results in enhanced papilloma formation or causes tumors without promotion [10,11]. A recent report showed that enhanced epidermal ODC expression converts the tumor promotion‐resistant mouse strain C57BL/6 to a promotion‐sensitive phenotype [12]. Taken together, these results support the hypothesis that ODC plays a critical role in carcinogenesis.…”

The upregulation of peripheral blood polyamine metabolites spermidine and spermine in children with hand, foot, mouth disease is related to enterovirus 71 capsid protein VP1, but not VP4

“…Further, ODC1, a key enzyme of polyamines, is important for tumor progression. The overexpression of ODC1 profoundly interferes with skin homeostasis and can lead to tumor development in mice ( 40 - 43 ). Nilsson et al ( 44 ) inhibited ODC1 by difluoromethylornithine (DFMO) affected Myc-mediated proliferation during tumorigenesis and markedly delayed the development of lymphoma, which suggests that ODC1 could be an effective target for cancer chemoprevention.…”

Vitamin D3 receptor ablation sensitizes skin to chemically induced tumorigenesis

“…Further studies will be necessary to determine if sensitivity to topically applied DMBA differs between VDR ablated mice and their wild-type controls. Mice transgenic for ornithine decarboxylase (ODC), another hairlesslike phenotypic mutant, exhibit alopecia and, like VDR -/mice, display enhanced sensitivity to skin tumorigenesis (24,25). The similarity of ODC transgenic mice and VDR -/mice is particularly interesting since vitamin D analog inhibition of skin carcinogenesis is associated with inhibition of ODC activation in skin (26).…”