American Association for Cancer Research
Browse

Supplementary Figure S4 from Inhibition of PORCN Blocks Wnt Signaling to Attenuate Progression of Oral Carcinogenesis

Download (15.34 MB)
journal contribution
posted on 2024-01-05, 08:20 authored by Daniel Peña-Oyarzún, Tania Flores, Vicente A. Torres, Andrew F.G. Quest, Lorena Lobos-González, Catalina Kretschmar, Pamela Contreras, Andrea Maturana-Ramírez, Alfredo Criollo, Montserrat Reyes

Effect of C59 on cell invasion in CAL-27 cells

Funding

Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT)

Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP)

Instituto Milenio en Inmunología e Inmunoterapia (MIII)

History

ARTICLE ABSTRACT

Oral squamous cell carcinoma (OSCC) is commonly preceded by potentially malignant lesions, referred to as oral dysplasia. We recently reported that oral dysplasia is associated with aberrant activation of the Wnt/β-catenin pathway, due to overexpression of Wnt ligands in a Porcupine (PORCN)-dependent manner. Pharmacologic inhibition of PORCN precludes Wnt secretion and has been proposed as a potential therapeutic approach to treat established cancers. Nevertheless, there are no studies that explore the effects of PORCN inhibition at the different stages of oral carcinogenesis. We performed a model of tobacco-induced oral cancer in vitro, where dysplastic oral keratinocytes (DOK) were transformed into oral carcinoma cells (DOK-TC), and assessed the effects of inhibiting PORCN with the C59 inhibitor. Similarly, an in vivo model of oral carcinogenesis and ex vivo samples derived from patients diagnosed with oral dysplasia and OSCC were treated with C59. Both in vitro and ex vivo oral carcinogenesis approaches revealed decreased levels of nuclear β-catenin and Wnt3a, as observed by immunofluorescence and IHC analyses. Consistently, reduced protein and mRNA levels of survivin were observed after treatment with C59. Functionally, treatment with C59 in vitro resulted in diminished cell migration, viability, and invasion. Finally, by using an in vivo model of oral carcinogenesis, we found that treatment with C59 prevented the development of OSCC by reducing the size and number of oral tumor lesions. The inhibition of Wnt ligand secretion with C59 represents a feasible treatment to prevent the progression of early oral lesions toward OSCC.