title: Downregulation of Wnt signaling by sonic hedgehog activation promotes repopulation of human tumor cell lines.
abstract: Tumor repopulation after radiotherapy is a big obstacle for clinical cancer therapy. The molecular mechanisms of tumor cell repopulation after radiotherapy remain unclear. This study investigated the role of sonic hedgehog (SHH) and Wnt signaling pathways in tumor repopulation after radiotherapy in an in vitro repopulation model. In this model, irradiated dying tumor cells functioned as feeder cells, whereas luciferase-labeled living tumor cells acted as reporter cells. Proliferation of reporter cells was measured by bioluminescence imaging. Results showed that irradiated dying HT29 and Panc1 tumor cells significantly stimulated the repopulation of living cells in their respective cultures. In HT29 and Panc1 cells, radiation significantly inhibited Wnt activity. In the irradiated dying HT29 and Panc1 cells, the level of the activated nuclear β-catenin was significantly decreased. Treatment with the Wnt agonist 68166 significantly decreased, whereas treatment with Wnt antagonist significantly increased, repopulation in HT29 and Panc1 tumor cells in a dose-dependent manner. β-catenin short-hairpin RNA (shRNA) also significantly promoted tumor cell repopulation. The level of secreted frizzled related protein-1 (SFRP1), hedgehog and Gli1 were increased in irradiated cells. Our results highlight the interaction between Wnt and SHH signaling pathways in dying tumor cells and suggest that downregulation of Wnt signaling after SHH activation is negatively associated with tumor repopulation.
authors.affiliation: The Comprehensive Cancer Center & Shanghai Key Laboratory for Pancreatic Diseases, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China. Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ma
authors.affiliation: The Comprehensive Cancer Center & Shanghai Key Laboratory for Pancreatic Diseases, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Experimental Research Center, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Experimental Research Center, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China. tl09168@hotmail.com qhuang2007@gmail.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.affiliation: The Comprehensive Cancer Center & Shanghai Key Laboratory for Pancreatic Diseases, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China. tl09168@hotmail.com qhuang2007@gmail.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
mesh_terms: D002452:Cell Count; D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D015398:Signal Transduction / Q000528:radiation effects; D060449:Wnt Signaling Pathway / Q000528:radiation effects; D014965:X-Rays
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D008156:Luciferases
keywords: Colon cancer; Pancreatic cancer; Radiotherapy; Repopulation; Wnt signaling