Elevated ZBTB7A expression in the tumor invasive front correlates with more tumor budding formation in gastric adenocarc
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ORIGINAL ARTICLE – CANCER RESEARCH
Elevated ZBTB7A expression in the tumor invasive front correlates with more tumor budding formation in gastric adenocarcinoma Yujing Sun1 · Junyi He2 · Duan‑Bo Shi2 · Hui Zhang2 · Xu Chen2 · Ai‑Yan Xing2 · Peng Gao1,2 Received: 23 June 2020 / Accepted: 5 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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-MAPKERK 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. Keywords Tumor budding · Gastric carcinoma · ZBTB7A · Epithelial-mesenchymal transition · Metastasis
Introduction Gastric cancer is one of the most lethal malignancies worldwide (Bray et al. 2018). Patients with early-stage gastric cancer usually have mild or no symptoms. Diagnosis is often made until advanced tumor stages. Although careful tumor staging, lymph node examination for a trace of metastasis Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00432-020-03388-3) contains supplementary material, which is available to authorized users. * Peng Gao [email protected] 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
Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
2
could help selecting appropriate treatment and predicting post-surgery outcome of the patients, tumor recurrence is still the main obstacle in cancer therapy. Tumor budding (TB) is defined as “the presence of cluste
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