Yiwen Xia1, Jialun Lv1, Tianlu Jiang1, Bowen Li1, Ying Li1, Zhongyuan He1, Zhe Xuan1, Guangli Sun1, Sen Wang1, Zheng Li1, Weizhi Wang1, Linjun Wang2, Zekuan Xu3,4. 1. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. 2. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. wanglinjun0616@163.com. 3. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. xuzekuan@njmu.edu.cn. 4. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China. xuzekuan@njmu.edu.cn.
Abstract
BACKGROUND: Circular RNAs (circRNAs) have emerged as a new subclass of regulatory RNAs that play critical roles in various cancers. Cancer stem cells (CSCs), a small subset of cancer cells, are believed to possess the capacities to initiate tumorigenesis and promote progression. Although accumulating evidence has suggested that cells with CSC-like properties are crucial for the malignancy of gastric cancer (GC), it remains unclear whether circRNAs are related to the acquisition of CSC-like properties in GC. METHODS: CircFAM73A expression was analyzed by GEO datasets and verified in GC samples. The roles of circFAM73A in GC cell proliferation, migration, cisplatin resistance, and CSC-like properties were determined by a series of functional experiments both in vitro and in vivo. RNA pulldown was used to explore the miRNAs and proteins binding to circFAM73A. Bioinformatic analysis and experimental verification confirmed the downstream targets of circFAM73A. The regulation of circFAM73A by HMGA2 was verified by ChIP and RIP assays. RESULTS: Elevated circFAM73A expression was confirmed in GC tissues, and higher circFAM73A predicted poor prognosis in GC patients. The upregulation of circFAM73A enhanced CSC-like properties in GC, thus facilitating cell proliferation, migration, and cisplatin resistance. Mechanistically, circFAM73A promoted GC malignancy by regulating miR-490-3p/HMGA2 in a positive feedback loop and recruiting HNRNPK to facilitate β-catenin stabilization. Moreover, HMGA2 further enhanced E2F1 and HNRNPL activity, which in turn promoted circFAM73A expression. CONCLUSIONS: Our work demonstrates the crucial role of circFAM73A in the CSC-like properties of GC and uncovers a positive feedback loop in circFAM73A regulation that leads to the progression of gastric cancer, which may provide new insights into circRNA-based diagnostic and therapeutic strategies.
BACKGROUND: Circular RNAs (circRNAs) have emerged as a new subclass of regulatory RNAs that play critical roles in various cancers. Cancer stem cells (CSCs), a small subset of cancer cells, are believed to possess the capacities to initiate tumorigenesis and promote progression. Although accumulating evidence has suggested that cells with CSC-like properties are crucial for the malignancy of gastric cancer (GC), it remains unclear whether circRNAs are related to the acquisition of CSC-like properties in GC. METHODS: CircFAM73A expression was analyzed by GEO datasets and verified in GC samples. The roles of circFAM73A in GC cell proliferation, migration, cisplatin resistance, and CSC-like properties were determined by a series of functional experiments both in vitro and in vivo. RNA pulldown was used to explore the miRNAs and proteins binding to circFAM73A. Bioinformatic analysis and experimental verification confirmed the downstream targets of circFAM73A. The regulation of circFAM73A by HMGA2 was verified by ChIP and RIP assays. RESULTS: Elevated circFAM73A expression was confirmed in GC tissues, and higher circFAM73A predicted poor prognosis in GCpatients. The upregulation of circFAM73A enhanced CSC-like properties in GC, thus facilitating cell proliferation, migration, and cisplatin resistance. Mechanistically, circFAM73A promoted GCmalignancy by regulating miR-490-3p/HMGA2 in a positive feedback loop and recruiting HNRNPK to facilitate β-catenin stabilization. Moreover, HMGA2 further enhanced E2F1 and HNRNPL activity, which in turn promoted circFAM73A expression. CONCLUSIONS: Our work demonstrates the crucial role of circFAM73A in the CSC-like properties of GC and uncovers a positive feedback loop in circFAM73A regulation that leads to the progression of gastric cancer, which may provide new insights into circRNA-based diagnostic and therapeutic strategies.
Authors: Christin E Burd; William R Jeck; Yan Liu; Hanna K Sanoff; Zefeng Wang; Norman E Sharpless Journal: PLoS Genet Date: 2010-12-02 Impact factor: 5.917
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