Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice

Area of Science:

• Oncology
• Genetics
• Dermatology

Background:

• C57BL/6 mice are resistant to Ras-induced skin squamous cell carcinomas (SCCs), while FVB/N mice are susceptible.
• The genetic basis for this differential susceptibility to SCC development is currently unknown.

Purpose of the Study:

• To investigate the genetic factors underlying the differential susceptibility of mouse strains to Ras-induced SCCs.
• To identify the specific gene and its polymorphism responsible for controlling SCC development.

Main Methods:

• Utilized C57BL/6 and FVB/N mouse strains and their F1 hybrids in experiments involving Ras oncogene induction.
• Genetically manipulated the Patched (Ptch) gene, including allele elimination and overexpression in epidermal cells of transgenic mice.
• Assessed tumor development, apoptosis, and gene signaling pathways, including Sonic Hedgehog (SHH).

Main Results:

• Susceptibility to SCC is controlled by a carboxy-terminal polymorphism in the mouse Ptch gene.
• Eliminating the C57BL/6 Ptch allele or overexpressing the FVB/N Ptch allele in hybrid mice overcame resistance to SCCs.
• SCCs in affected mice did not show loss of the wild-type Ptch gene or increased SHH signaling, suggesting a role in early lineage commitment.

Conclusions:

• A Ptch gene polymorphism critically influences susceptibility to Ras-induced SCCs.
• Ptch plays a role in determining basal or squamous cell lineage, impacting tumor type based on genetic background and carcinogen exposure.
• The Ptch polymorphism affects Hras-induced apoptosis and interaction with the Tid1 tumor suppressor.