TERMINAL DIFFERENTIATION REGULATED BY ALK5 IN PRENEOPLASTIC KERATINOCYTES
Open Access
- Author:
- Masiuk, Katelyn
- Area of Honors:
- Biochemistry and Molecular Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Adam Bleier Glick, Thesis Supervisor
Adam Bleier Glick, Thesis Supervisor
Chen Pei David Tu, Thesis Honors Advisor
Jeffrey Maurice Peters, Faculty Reader
Dr. Wendy Hanna-Rose, Faculty Reader - Keywords:
- TGFβ. skin cancer
differentiation - Abstract:
- Genetic studies investigating Transforming Growth Factor β (TGFβ) have revealed a dual role for TGFβ in cancer progression, with TGFβ acting as an early tumor suppressor and later acting as an oncogene. Contrary to this established paradigm, we have previously shown in a two-stage chemical carcinogenesis model that pharmacological inhibition of the TGFβ type I receptor (ALK5) by SB431542 (SB) inhibits papilloma formation and enhances malignant progression of papillomas that do form. Here we investigate altered terminal differentiation in premalignant keratinocytes as a potential mechanism by which ALK5 inhibition could decrease papilloma formation. SB treatment of HRAS expressing keratinocytes shows an increase in cornification that correlates with increased expression of terminal differentiation genes transglutaminase 1 (TGM1) and 3 (TGM3) and small proline-rich protein 1A (SPR1A) and 2H (SPR2H). Conversely, treatment with TGFβ1 decreases expression of these genes and inhibits cornification in HRAS expressing keratinocytes. These results are also observed in vivo, as mice expressing HRAS in basal keratinocytes that are treated with SB show increased epidermal thickness and increased expression of TGM1/3 and SPR1A/2H. Together, these results suggest that induction of terminal differentiation may be a potential mechanism by which pharmacological inhibition of TGFβ signaling inhibits early papilloma formation in a premalignant, HRAS expressing model.