Effect of IGF2BP1 inhibition on Wnt and hedgehog (Hh) signaling in basal cell carcinoma (BCC)

Summary: Abstract Body: The insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an RNA-binding protein that we previously identified as a bona fide transcriptional target of the Wnt/β-catenin signaling pathway. We also showed that IGF2BP1 regulates the transcriptional activator of the Hh pathway GLI1 and serves as a mechanistic link in the crosstalk between Wnt and Hh pathways. IGF2BP1 induction has been shown to regulate other genes promoting the development of metastasis. As constitutive activation of the Hh signaling pathway was shown to drive basal cell carcinoma (BCC) development, we hypothesized that inhibition of IGF2BP1 will reduce GLI1 expression and activity and therefore prevent BCC development. To test our hypothesis, we used a mouse model of BCC (Ptch1+/-). We also used UW-BCC1 cells to generate xenograft tumors in immunocompromised mice (Foxn1nu). We determined the effects of IGF2BP1 inhibition on tumor growth in immunocompromised mice and in the development of BCC-like lesions in Ptch1+/- mice. The expression of Wnt and Hh targets was also assessed. We found that inhibition of IGF2BP1 in UW-BCC1 cells significantly reduced tumor growth in xenograft mice compared to controls (P<0.05). In Ptch1+/- mice, skin specific IGF2BP1 knockout significantly reduced the number of lesions in those mice compared to the control mice after their prolonged exposure to 240 mJ/cm2 UVB irradiation (P<0.05). Inhibition of IGF2BP1 also significantly reduced the expression of Wnt and Hh targets analyzed in this study. IGF2BP1 appears to contribute to BCC development and might represent a novel target in the management or treatment of this disease. Cayla Harris¹, Mohammed Hajahmed¹, Joshua Herron¹, Clement Yedjou³, Vladimir Spiegelman⁴, Oluwatoyin Odubanjo¹, Jean Christopher Chamcheu⁵, Tithi Roy⁶, Samuel Boetang², Roxane Chamcheu², Felicite Noubissi¹ 1. Jackson State University, Jackson, MS, United States. 2. The University of Louisiana Monroe College of Pharmacy, Monroe, LA, United States. 3. Florida Agricultural and Mechanical University, Tallahassee, FL, United States. 4. The Pennsylvania State University, University Park, PA, United States. 5. Southern University and A&M College, Baton Rouge, LA, United States. 6. University of California System, Oakland, CA, United States. UV Biology/Injury and Non-melanoma Cancers