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
  • Chen Pei David Tu, Honors Advisor
  • Jeffrey Maurice Peters, Faculty Reader
  • 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.