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Published on: December 19, 2019
Unexpected roles for pRb in mouse skin carcinogenesis
Sergio Ruiz1, Mirentxu Santos, M Fernanda Lara
1Program on Cell and Molecular Biology, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas and Department of Pathology, Hospital 12 de Octubre, Madrid, Spain.
Abstract:
The mouse skin carcinogenesis represents one of the best models for the understanding of malignant transformation, including the multistage nature of tumor development. The retinoblastoma gene product (pRb) plays a critical role in cell cycle regulation, differentiation, and inhibition of oncogenic transformation. In epidermis, Rb-/- deletion leads to proliferation and differentiation defects. Numerous evidences showed the involvement of the retinoblastoma pathway in this model. However, the actual role of pRb is still unknown. To study the possible involvement of pRb in keratinocyte malignant transformation, we have carried out two-stage chemical skin carcinogenesis on Rb(F19/F19) (thereafter Rb+/+) and Rb(F19/F19);K14Cre (thereafter Rb-/-) animals. Unexpectedly, we found that Rb-/- mice developed fewer and smaller papillomas than the Rb+/+ counterparts. Moreover, the small size of the pRb-deficient tumors is associated with an increase in the apoptotic index. Despite this, pRb-deficient tumors display an increased conversion rate to squamous cell carcinomas. Biochemical analyses revealed that these characteristics correlate with the differential expression and activity of different pathways, including E2F/p19arf/p53, PTEN/Akt, c-jun NH2-terminal kinase/p38, and nuclear factor-kappaB. Collectively, our findings show unexpected and hitherto nondescribed roles of pRb during the process of epidermal carcinogenesis.
Insights
The retinoblastoma gene product (pRb) surprisingly reduced papilloma size and increased apoptosis in mouse skin cancer models. However, pRb deficiency accelerated malignant progression to squamous cell carcinomas, revealing novel roles in epidermal carcinogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Mouse skin carcinogenesis is a key model for understanding tumor development.
- The retinoblastoma gene product (pRb) is crucial for cell cycle regulation and tumor suppression.
- The specific role of pRb in epidermal carcinogenesis remains unclear.
Purpose of the Study:
- To investigate the role of pRb in keratinocyte malignant transformation using a mouse skin carcinogenesis model.
- To elucidate the impact of pRb deletion on tumor development, progression, and associated molecular pathways.
Main Methods:
- Two-stage chemical skin carcinogenesis was performed on wild-type (Rb+/+) and pRb-deficient (Rb-/-) mice.
- Tumor incidence, size, and apoptotic index were analyzed.
- Biochemical analyses assessed the activity of key signaling pathways (E2F/p19arf/p53, PTEN/Akt, JNK/p38, NF-kappaB).
Main Results:
- Rb-/- mice exhibited fewer and smaller papillomas with increased apoptosis compared to Rb+/+ mice.
- Despite reduced size, pRb-deficient tumors showed a higher conversion rate to squamous cell carcinomas.
- Differential expression and activity of signaling pathways were observed in pRb-deficient tumors.
Conclusions:
- pRb plays an unexpected role in regulating papilloma size and apoptosis during skin carcinogenesis.
- Loss of pRb paradoxically promotes malignant progression to squamous cell carcinoma.
- These findings reveal novel functions of pRb in epidermal carcinogenesis and associated signaling networks.
