Abstract
Abstract Background Colorectal cancer (CRC) is one of the deadliest cancers in the world. Increasing evidence suggests that circular RNAs (circRNAs) are implicated in CRC pathogenesis. This study aimed to determine the role of circAPLP2 and explore a potential mechanism of circAPLP2 action in CRC. Methods The expression of circAPLP2, miR-335-5p and helicase lymphoid-specific (HELLS) mRNA in CRC tissues and cells was measured by quantitative real-time polymerase chain reaction (qPCR). The functional effects of circAPLP2 on cell cycle progression/cell apoptosis, colony formation, cell migration, invasion and glycolysis metabolism were investigated by flow cytometry assay, colony formation assay, wound healing assay, transwell assay and glycolysis stress test. Glycolysis metabolism was also assessed by the levels of glucose uptake and lactate production. The protein levels of HELLS and HK2 were detected by western blot. The interaction between circAPLP2 and miR-335-5p, or miR-335-5p and HELLS was verified by dual-luciferase reporter assay. The role of circAPLP2 on solid tumor growth in nude mice was investigated. Results circAPLP2 and HELLS were overexpressed, but miR-335-5p was downregulated in CRC tissues and cells. Functional analyses showed that circAPLP2 knockdown suppressed CRC cell cycle progression, colony formation, migration, invasion and glycolysis metabolism, induced cell apoptosis and blocked solid tumor growth in nude mice. Moreover, miR-335-5p was a target of circAPLP2, and miR-335-5p could also bind to HELLS. Rescue experiments presented that miR-335-5p inhibition reversed the effects of circAPLP2 knockdown, and HELLS overexpression abolished the role of miR-335-5p restoration. Importantly, circAPLP2 could positively regulate HELLS expression by mediating miR-335-5p. Conclusion circAPLP2 triggered CRC malignant development by increasing HELLS expression via targeting miR-335-5p, which might be a novel strategy to understand and treat CRC.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related death, second only to lung cancer, liver cancer and stomach cancer [1]
CircRNA expression profile revealed that circDDX17 was notably downregulated in CRC tissues, and low expression of circDDX17 contributed to CRC cell proliferation, migration and invasion [12]
CircBANP was presented to be upregulated in CRC tissues by circRNA expression profile, and circBANP knockdown suppressed CRC cell proliferation and served as a prognostic and therapeutic marker [21]
Summary
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related death, second only to lung cancer, liver cancer and stomach cancer [1]. CRC is the second common cancer in females and the third most common cancer in males [2]. Mutations in specific genes contribute to CRC, just like other types of cancer. These mutations can appear in oncogenes, tumor suppressor genes and genes related to DNA repair mechanisms [1]. The dysregulation of circular RNAs (circRNAs) in cancers has aroused much concern [5].
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