miR-4999-5p Predicts Colorectal Cancer Survival Outcome and Reprograms Glucose Metabolism by Targeting PRKAA2

PURPOSE: Colorectal cancer (CRC) is the third most common cancer, and the second leading cause of cancer death worldwide. Dysregulation of microRNAs has been shown to modulate glucose metabolic reprogramming in CRC. However, the functional role of miR-4999-5p in the CRC glucose metabolic shift has not been characterized. PATIENTS AND METHODS: The levels of miR-4999-5p and PRKAA2 were evaluated by RT-qPCR. Univariate and multivariate survival analyses were conducted to evaluate the prognostic value of miR-4999-5p. Cell proliferation was assessed using the CCK-8 and colony formation assays. Extracellular acidification rate, glucose uptake, cellular glucose-6-phosphate level, and lactate production were evaluated to assess the effects of miR-4999-5p on CRC glycolysis. Dual-luciferase reporter assay was conducted to investigate the direct interaction between miR-4999-5p and PRKAA2. Mouse xenograft models were established to assess the functions of miR-4999-5p in vivo. RESULTS: miR-4999-5p was highly expressed in CRC tissues and cell lines. In addition, miR-4999-5p was associated with tumor differentiation and TNM stage, and elevated expression of miR-4999-5p was an independent predictor of poorer overall survival. Furthermore, miR-4999-5p promoted cell proliferation and glycolysis in CRC. miR-4999-5p targeted PRKAA2 to exert its tumor-promoting functions, and PRKAA2 knockdown rescued decreased cell proliferation and glycolysis in miR-4999-5p-silenced CRC cells. In vivo experiments showed that miR-4999-5p promoted CRC growth. CONCLUSION: miR-4999-5p facilitated cell growth and glucose metabolic reprogramming through direct targeting of PRKAA2. Our results showed that miR-4999-5p may be a novel prognostic marker and therapeutic target for CRC.