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Targeted deletion of RasGRP1 impairs skin tumorigenesis
Amrish Sharma1, Lauren L Fonseca, Cynthia Rajani
1Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
Abstract:
Ras is frequently activated in cutaneous squamous cell carcinoma, a prevalent form of skin cancer. However, the pathways that contribute to Ras-induced transformation have not been entirely elucidated. We have previously demonstrated that in transgenic mice, overexpression of the Ras activator RasGRP1 promotes the formation of spontaneous skin tumors and enhances malignant progression in the multistage carcinogenesis skin model that relies on the oncogenic activation of H-Ras. Utilizing a RasGRP1 knockout mouse model (RasGRP1 KO), we now show that lack of RasGRP1 reduced the susceptibility to skin tumorigenesis. The dependency on RasGRP1 was associated with a diminished response to the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Specifically, we found impairment of epidermal hyperplasia induced by TPA through keratinocyte proliferation. Using a keratinocyte cell line that carries a ras oncogenic mutation, we also demonstrated that RasGRP1 could further activate Ras in response to TPA. Thus, we propose that RasGRP1 upregulates signaling from Ras and contributes to epidermal tumorigenesis by increasing the total dosage of active Ras.
Insights
RasGRP1 is crucial for skin tumor development. Its absence reduces susceptibility to skin cancer by impairing Ras signaling and keratinocyte proliferation, highlighting RasGRP1
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Ras activation is common in cutaneous squamous cell carcinoma.
- The precise mechanisms of Ras-driven transformation remain incompletely understood.
Purpose of the Study:
- To investigate the role of RasGRP1 in Ras-induced skin tumorigenesis.
- To determine the impact of RasGRP1 deficiency on skin cancer development and response to tumor promoters.
Main Methods:
- Utilized a RasGRP1 knockout mouse model.
- Assessed susceptibility to skin tumorigenesis and response to 12-O-tetradecanoylphorbol-13-acetate (TPA).
- Examined keratinocyte proliferation and Ras activation in response to TPA.
Main Results:
- RasGRP1 knockout mice showed reduced susceptibility to skin tumorigenesis.
- Lack of RasGRP1 diminished the response to the tumor promoter TPA.
- RasGRP1 was found to further activate Ras in oncogenic keratinocytes upon TPA stimulation, impairing epidermal hyperplasia.
Conclusions:
- RasGRP1 plays a significant role in promoting epidermal tumorigenesis.
- RasGRP1 contributes to skin cancer by upregulating Ras signaling and increasing active Ras levels.
- Targeting RasGRP1 may offer a therapeutic strategy for cutaneous squamous cell carcinoma.
![Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F60445.jpg&w=3840&q=50)
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