Metformin Inhibits the Development of Hypopharyngeal Squamous Cell Carcinoma through Circ_0003214-Mediated MiR-489-3p-ADAM10 Pathway

Abstract

Purpose. This study aims to explore the function of metformin in hypopharyngeal squamous cell carcinoma (HSCC) and the underlying mechanism. Methods. Cell viability, colony formation, cell apoptosis, and cell cycle were investigated using cell counting kit-8 assay, colony formation, and flow cytometry assay. Gene expression was detected by quantitative real-time polymerase chain reaction and western blot. The target relationship was validated by dual-luciferase reporter assay or RNA immunoprecipitation assay. An animal study was implemented to clarify the effect of metformin in vivo. Results. Metformin suppressed HSCC cell viability and colony formation ability and induced cell cycle arrest and apoptosis, and circ_0003214 overexpression weakened these effects. Circ_0003214 regulated A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) expression via targeting miR-489-3p. Besides, miR-489-3p restoration reversed the role of circ_0003214, and ADAM10 knockdown reversed miR-489-3p inhibition-mediated effect. Moreover, metformin blocked tumor growth via the circ_0003214-miR-489-3p-ADAM10 axis in vivo. Conclusion. Metformin inhibits HSCC progression through the circ_0003214/miR-489-3p/ADAM10 pathway.

The mechanisms of action of metformin on head and neck cancer in the pre-clinical setting: a scoping review

“…Metformin was also found to target circular RNAs (circRNA) which regulate miRNAs ( 95 ). Circ_0003214 was noted to be highly expressed while tumor suppressor miR-489-3p was under-expressed in HNSCC ( 95 ). Increased level of ADAM10 in OSCC is reported to contribute to migration and invasion ( 96 ).…”

“…Increased level of ADAM10 in OSCC is reported to contribute to migration and invasion ( 96 ). Metformin reduces circ_0003214 which subsequently increases miR-489-3p and reduces its target ADAM10 ( 95 ) ( Figure 10 ). This was reflected in the reduction of cell viability and colony formation in vitro and reduced tumor weight and volume in vivo ( 95 ).…”

“…Metformin was also found to target circular RNAs (circRNA) which regulate miRNAs (95). Circ_0003214 was noted to be highly expressed while tumor suppressor miR-489-3p was underexpressed in HNSCC (95).…”