title: APR-246/PRIMA-1Met Inhibits and Reverses Squamous Metaplasia in Human Conjunctival Epithelium.
abstract: OBJECTIVE
  Squamous metaplasia is a common pathologic condition in ocular surface diseases for which there is no therapeutic medication in clinic. In this study, we investigated the effect of a small molecule, APR-246/PRIMA-1(Met), on squamous metaplasia in human conjunctival epithelium.
  
  
  METHODS
  Human conjunctival explants were cultured for up to 12 days under airlifting conditions. Epithelial cell differentiation and proliferation were assessed by Cytokeratin 10 (K10), K14, K19, Pax6, MUC5AC, and p63 immunostaining patterns. β-catenin and TCF-4 immunofluorescent staining and real-time PCR characterized Wnt signaling pathway involvement. Pterygium clinical samples were cultured under airlifting conditions with or without APR-246 for 4 days. p63, K10, β-catenin, and TCF-4 expression in pterygial epithelium was determined by immunofluorescent staining and real-time PCR.
  
  
  RESULTS
  Airlift conjunctival explants resulted in increased stratification and intrastromal epithelial invagination. Such pathology was accompanied by increases in K10, K14, and p63 expression, whereas K19 and Pax6 levels declined when compared to those in freshly isolated tissue. On the other hand, APR-246 reversed all of these declines in K10, K14, and p63 expression. Furthermore, K19 and Pax6 increased along with rises in goblet cell density. These effects of APR-246 were accompanied by near restoration of normal conjunctival epithelial histology. APR-246 also reversed squamous metaplasia in pterygial epithelium that had developed after 4 days in ex vivo culture.
  
  
  CONCLUSIONS
  Reductions in squamous metaplasia induced by APR-246 suggest it may provide a novel therapeutic approach in different squamous metaplasia-associated ocular surface diseases.
authors: Eye Institute of Xiamen University Xiamen, Fujian, China 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Jing
authors: J
authors: Li
authors: Eye Institute of Xiamen University Xiamen, Fujian, China 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Cheng
authors: C
authors: Li
authors: Eye Institute of Xiamen University Xiamen, Fujian, China 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Guoliang
authors: G
authors: Wang
authors: Eye Institute of Xiamen University Xiamen, Fujian, China 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Zhen
authors: Z
authors: Liu
authors: Eye Institute of Xiamen University Xiamen, Fujian, China 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Pei
authors: P
authors: Chen
authors: Eye Institute of Xiamen University Xiamen, Fujian, China 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China.
authors: Qichen
authors: Q
authors: Yang
authors: Xiamen University Affiliated Xiamen Eye Center, Xiamen, Fujian, China.
authors: Nuo
authors: N
authors: Dong
authors: Xiamen University Affiliated Xiamen Eye Center, Xiamen, Fujian, China.
authors: Huping
authors: H
authors: Wu
authors: Eye Institute of Xiamen University Xiamen, Fujian, China 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China 3Xiamen University Affiliated Xiamen Eye Center, Xiamen, Fujian, China.
authors: Zuguo
authors: Z
authors: Liu
authors: Eye Institute of Xiamen University Xiamen, Fujian, China 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China 3Xiamen University Affiliated Xiamen Eye Center, Xiamen, Fujian, China.
authors: Wei
authors: W
authors: Li
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D054338:Cell Transdifferentiation / Q000187:drug effects*; D003228:Conjunctiva / Q000378:metabolism / Q000473:pathology*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D053550:Keratin-10 / Q000378:metabolism; D008679:Metaplasia; D009924:Organ Culture Techniques; D011625:Pterygium / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011812:Quinuclidines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers; C507493:KRT10 protein, human; D011812:Quinuclidines; C532096:TCF4 protein, human; C115051:TP63 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D053550:Keratin-10; C533410:eprenetapopt