PMID- 37812478 OWN - NLM STAT- MEDLINE DCOM- 20240108 LR - 20240314 IS - 1557-3265 (Electronic) IS - 1078-0432 (Linking) VI - 30 IP - 1 DP - 2024 Jan 5 TI - Inhibition of PORCN Blocks Wnt Signaling to Attenuate Progression of Oral Carcinogenesis. PG - 209-223 LID - 10.1158/1078-0432.CCR-23-0318 [doi] AB - PURPOSE: 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/beta-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. EXPERIMENTAL DESIGN: 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. RESULTS: Both in vitro and ex vivo oral carcinogenesis approaches revealed decreased levels of nuclear beta-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. CONCLUSIONS: The inhibition of Wnt ligand secretion with C59 represents a feasible treatment to prevent the progression of early oral lesions toward OSCC. CI - (c)2023 American Association for Cancer Research. FAU - Pena-Oyarzun, Daniel AU - Pena-Oyarzun D AUID- ORCID: 0000-0001-8881-8074 AD - Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. AD - Physiology Department, Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile. AD - Interdisciplinary Center for Research in Territorial Health of the Aconcagua Valley (CIISTe Aconcagua), School of Medicine, Faculty of Medicine, San Felipe Campus, Universidad de Valparaiso, Chile. FAU - Flores, Tania AU - Flores T AUID- ORCID: 0000-0001-7582-6278 AD - Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. AD - Research Centre in Dental Science (CICO), Faculty of Dentistry, Universidad de La Frontera, Temuco, Chile. AD - Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. FAU - Torres, Vicente A AU - Torres VA AUID- ORCID: 0000-0002-5973-7248 AD - Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. AD - Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. AD - Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, Santiago, Chile. FAU - Quest, Andrew F G AU - Quest AFG AUID- ORCID: 0000-0001-8755-1590 AD - Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. AD - Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, Universidad de Chile, Santiago, Chile. FAU - Lobos-Gonzalez, Lorena AU - Lobos-Gonzalez L AUID- ORCID: 0000-0002-4957-9864 AD - Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. AD - Center for Regenerative Medicine, Faculty of Medicine, Clinica Alemana-Universidad del Desarrollo, Santiago, Chile. FAU - Kretschmar, Catalina AU - Kretschmar C AUID- ORCID: 0000-0002-2365-6251 AD - Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. FAU - Contreras, Pamela AU - Contreras P AUID- ORCID: 0009-0007-2647-916X AD - Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. AD - Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, Universidad de Chile, Santiago, Chile. FAU - Maturana-Ramirez, Andrea AU - Maturana-Ramirez A AUID- ORCID: 0000-0001-5459-2361 AD - Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. FAU - Criollo, Alfredo AU - Criollo A AUID- ORCID: 0000-0002-2737-7751 AD - Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. AD - Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. FAU - Reyes, Montserrat AU - Reyes M AUID- ORCID: 0000-0002-4116-4074 AD - Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. LA - eng GR - 11221000/Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT)/ GR - 3200313/Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT)/ GR - 1220517/Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT)/ GR - 1210644/Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT)/ GR - 1211329/Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT)/ GR - 1211223/Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT)/ GR - 15130011/Fondo de Financiamiento de Centros de Investigacion en Areas Prioritarias (FONDAP)/ GR - ICN09_016/ICN 2021_045/Instituto Milenio en Inmunologia e Inmunoterapia (MIII)/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (beta Catenin) RN - EC 2.3.1.- (PORCN protein, human) RN - EC 2.3.- (Acyltransferases) RN - 0 (Membrane Proteins) SB - IM MH - Humans MH - Wnt Signaling Pathway MH - *Carcinoma, Squamous Cell/drug therapy/genetics MH - beta Catenin/genetics/metabolism MH - *Mouth Neoplasms/drug therapy MH - Squamous Cell Carcinoma of Head and Neck MH - *Head and Neck Neoplasms MH - Carcinogenesis/genetics MH - Acyltransferases/metabolism/pharmacology MH - Membrane Proteins/metabolism EDAT- 2023/10/09 12:42 MHDA- 2024/01/08 06:42 CRDT- 2023/10/09 11:53 PHST- 2023/02/01 00:00 [received] PHST- 2023/05/12 00:00 [revised] PHST- 2023/10/05 00:00 [accepted] PHST- 2024/01/08 06:42 [medline] PHST- 2023/10/09 12:42 [pubmed] PHST- 2023/10/09 11:53 [entrez] AID - 729528 [pii] AID - 10.1158/1078-0432.CCR-23-0318 [doi] PST - ppublish SO - Clin Cancer Res. 2024 Jan 5;30(1):209-223. doi: 10.1158/1078-0432.CCR-23-0318.