Yujing Sun1, Junyi He2, Duan-Bo Shi2, Hui Zhang2, Xu Chen2, Ai-Yan Xing2, Peng Gao3,4. 1. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China. 2. Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China. 3. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China. gaopeng@sdu.edu.cn. 4. Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China. gaopeng@sdu.edu.cn.
Abstract
PURPOSE: Tumor budding (TB) is reported to predict nodal involvement and recurrence in multiple human malignancies. However, it is not clear how TB forms. The purpose of this study is to find markers related to TB formation in gastric cancer and to investigate the underlying mechanisms. METHODS: TB was scored on hematoxylin-eosin staining slides in 122 gastric cancer cases. Immunostaining score of CREB1, GAGE12I, CTNND1, KIF26B and ZBTB7A both at the invasive front and in the center of the tumor were assigned to each case. Spearman's correlation with the TB score was performed to find the TB-related markers. In vitro study and RNA-seq using gastric cancer cell lines were done to unveil the mechanisms. RESULTS: TB could predict lymph node metastasis and is negatively associated with overall survival of the patients. The expression of ZBTB7A in the invasive front, rather than the other four markers, was much higher than that in the tumor center and was positively correlated with TB score. ZBTB7A could enhance migration and invasion of gastric cancer cells in vitro. RNA-seq data followed by RT-qPCR and western blot verification demonstrated the activation of EGFR-MAPK-ERK and PI3K-AKT-mTOR pathways and increased expression of EMT related markers upon ZBTB7A over-expression. CONCLUSION: Higher ZBTB7A expression in the tumor margin may contribute to the dissociation of tumor cells from the tumor mass to form TB by initiating EMT via EGFR-MEK-ERK and PI3K-AKT-mTOR pathway.
PURPOSE:Tumor budding (TB) is reported to predict nodal involvement and recurrence in multiple humanmalignancies. However, it is not clear how TB forms. The purpose of this study is to find markers related to TB formation in gastric cancer and to investigate the underlying mechanisms. METHODS:TB was scored on hematoxylin-eosin staining slides in 122 gastric cancer cases. Immunostaining score of CREB1, GAGE12I, CTNND1, KIF26B and ZBTB7A both at the invasive front and in the center of the tumor were assigned to each case. Spearman's correlation with the TB score was performed to find the TB-related markers. In vitro study and RNA-seq using gastric cancer cell lines were done to unveil the mechanisms. RESULTS:TB could predict lymph node metastasis and is negatively associated with overall survival of the patients. The expression of ZBTB7A in the invasive front, rather than the other four markers, was much higher than that in the tumor center and was positively correlated with TB score. ZBTB7A could enhance migration and invasion of gastric cancer cells in vitro. RNA-seq data followed by RT-qPCR and western blot verification demonstrated the activation of EGFR-MAPK-ERK and PI3K-AKT-mTOR pathways and increased expression of EMT related markers upon ZBTB7A over-expression. CONCLUSION: Higher ZBTB7A expression in the tumor margin may contribute to the dissociation of tumor cells from the tumor mass to form TB by initiating EMT via EGFR-MEK-ERK and PI3K-AKT-mTOR pathway.
Authors: Eva Karamitopoulou; Inti Zlobec; Ioannis Panayiotides; Efstratios S Patsouris; George Peros; George Rallis; Christos Lapas; Petros Karakitsos; Luigi M Terracciano; Alessandro Lugli Journal: Hum Pathol Date: 2011-06-12 Impact factor: 3.466
Authors: Eva Karamitopoulou; Alessandro Lugli; Ioannis Panayiotides; Petros Karakitsos; George Peros; George Rallis; Efstratios S Patsouris; Luigi Terracciano; Inti Zlobec Journal: Histopathology Date: 2010-08 Impact factor: 5.087