CircFAM73A promotes the cancer stem cell-like properties of gastric cancer through the miR-490-3p/HMGA2 positive feedback loop and HNRNPK-mediated β-catenin stabilization.

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.

• Authors: Yiwen Xia, Jialun Lv, Tianlu Jiang, Bowen Li, Ying Li, Zhongyuan He, Zhe Xuan, Guangli Sun, Sen Wang, Zheng Li, Weizhi Wang, Linjun Wang, Zekuan Xu
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 40 Issue 1 Pg. 103 (Mar 17 2021) ISSN: 1756-9966 [Electronic] England
• PMID: 33731207 (Publication Type: Journal Article)

Chemical References

• CTNNB1 protein, human
• HMGA2 Protein
• HMGA2 protein, human
• Heterogeneous-Nuclear Ribonucleoprotein K
• MIRN490 microRNA, human
• MicroRNAs
• RNA, Circular
• beta Catenin
• HNRNPK protein, human
• Cisplatin

Topics

• Animals
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Disease Progression
• Drug Resistance, Neoplasm
• Feedback, Physiological
• Female
• HMGA2 Protein (genetics, metabolism)
• Heterogeneous-Nuclear Ribonucleoprotein K (genetics, metabolism)
• Heterografts
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Neoplastic Stem Cells (metabolism, pathology)
• RNA, Circular (genetics, metabolism)
• Stomach Neoplasms (genetics, metabolism, pathology)
• Up-Regulation
• beta Catenin (metabolism)