한빛사논문
- 조회580
Jun Lu1,2*, Long-long Cao1*, Yu Xu3*, Xiao-yan Huang1, Soo-Jeong Cho4, Hassan
Ashktorab5, Duane T. Smoot5, Ping Li1, Chao-hui Zheng1, Ji-Won Kim6, Sandra W. Ryeom7, Sam S. Yoon2, Changhwan Yoon2#, Chang-ming Huang1#
1Department of Gastric Surgery, Department of General Surgery, Fujian Medical
University Union Hospital, Fuzhou, Fujian Province, China,350001
2Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10013
3Department of Pathology, School of Basic Medical Sciences, Fujian Medical,35001 University, Fuzhou, Fujian Province, China,35001
4Department of Internal Medicine, Liver Research Institute, Seoul National University
Hospital, Seoul, South Korea, 100-000
5Department of Medicine, Howard University, Washington, DC, 20541
6Division of Hematology and Medical Oncology, Department of Internal Medicine Seoul National University Bundang Hospital, Gyeonggi-do, South Korea, 100-000
7Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19019
*These authors contributed equally to this work.
#Correspondence: Changhwan Yoon, PhD, Chang-ming Huang, MD
Abstract
Chemoresistance is the major cause of gastric adenocarcinoma (GA) treatment failure. The mechanisms underlying chemoresistance remain incompletely understood. Here, we sought to identify genes differentially expressed between chemoresistant and chemosensitive GA and to validate the function of the top hit.
High-throughput RNA sequencing was performed to detect chemoresistance-related genes. The function of the only gene overexpressed in both chemoresistant tumors and tumor tissue relative to normal gastric epithelia, FOXC1, was examined in GA cells, mouse xenograft models, and patient-derived organoid (PDO) systems, focusing on cancer stem-like cell (CSC) phenotypes, metastasis, and chemoresistance. FOXC1 was expressed at significantly higher levels in GA patient tumors that were resistant to chemotherapy, and high FOXC1 tumor expression was significantly correlated with poor survival among patients undergoing resection (p=0.011). FOXC1 activity was significantly higher in spheroid-forming or CD44+ GA CSCs than in unselected cells. Inhibition of FOXC1 decreased the expression of CD44 and Sox2, decreased spheroid size by 78-82%, and decreased spheroid number (>100 μm) by 75–86%. GA CSC chemotherapy resistance was reversed with FOXC1 inhibition in vitro, in vivo, and in patient-derived organoids (PDOs). Mechanistic studies indicated that FOXC1 acts via the Hedgehog and epithelial-to-mesenchymal transition (EMT) pathways. Our results imply that FOXC1 mediates the CSC phenotypes, metastasis, and chemotherapy resistance of GA through Hedgehog and EMT signaling. FOXC1 inhibitors may thus represent a novel strategy to overcome chemoresistance.
논문정보
- Research article
- 2021년 09월 (BRIC 등록일 2021-09-28)
- 국내+국외 연구진
- 의약학 > 종양의학
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