Abstract
BackgroundCircular 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.MethodsCircFAM73A 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.ResultsElevated 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.ConclusionsOur 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.
Highlights
Circular RNAs have emerged as a new subclass of regulatory RNAs that play critical roles in various cancers
Cancer stem cells (CSC) only account for a small proportion of cancer cells, they exhibit prominent features, including tumorigenesis, chemotherapy resistance, and high metastatic potential, which have been shown to be largely responsible for cancer metastasis, recurrence, and treatment failure [3, 4]
CircFAM73A is upregulated in GC, and high circFAM73A expression predicts poor prognosis To assess the Circular RNA (circRNA) involved in GC, we searched the circRNA datasets established for gastric cancer in the GEO datasets
Summary
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. 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. Cancer stem cells (CSCs) are defined as the fraction of cells that retain the capacities of self-renewal and differentiation [2]. CSCs only account for a small proportion of cancer cells, they exhibit prominent features, including tumorigenesis, chemotherapy resistance, and high metastatic potential, which have been shown to be largely responsible for cancer metastasis, recurrence, and treatment failure [3, 4]. The underlying regulatory mechanism of CSCs in GC remains to be elucidated
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