Lin28/let-7 Axis Plays A Key role in Regulating Aerobic Glycolysis and Cancer Progression in Hepatocellular Carcinoma via PDK1
Introduction. Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer in the world with a 5-year survival rate of only 5%, demonstrating the need for improved treatments1,2. Risk factors for HCC include alcohol consumption and diabetes, and it is usually a progression of cirrhosis1. All cancers exhibit the Warburg effect, a mechanism by which cancer cells alter their metabolism to preferentially undergo aerobic glycolysis instead of oxidative phosphorylation under normoxic conditions, which is less energetically favorable3. Studies have shown that Lin28 (RNA binding protein) inhibition of let-7 (tumor suppressor microRNA) promotes the Warburg effect in HCC, however, its mechanism for this is not well understood3,4,5. Understanding this mechanism could suggest potential new therapeutics for HCC5. Methods. Real-time PCR and Western blot analyses were used to determine the expression of Lin28 and let-7 in the Hep3B cell line from patients with HCC5. Glucose uptake and lactate production were measured in Hep3B cells overexpressing Lin28 and in cells with reduced let-7 expression via glucose and lactate assay kits respectively5. Cellular oxygen consumption was measured in these cells via a microelectrode using an Oxytherm unit5. PDK1 protein levels were measured using Western blot in Hep3B cells overexpressing Lin28 and let-75. Glucose uptake and lactate production were again measured in Heb3B cells with high PDK1 expression via assay kits5. Results. From RT-PCR, it was determined that Lin28 is overexpressed in HCC cells, thereby reducing let-7 expression5. The glucose, lactate, and oxygen assay showed a metabolic shift from oxidative phosphorylation to aerobic glycolysis via the Lin28/let-7 axis5. PDK1 was shown to be a direct target of Lin28 and let-7 and was upregulated in cells with high Lin28 expression and low let-7 expression, leading to decreased levels of pyruvate dehydrogenase5. Conclusions. Lin28 overexpression and reduced expression of let-7 upregulate PDK1, which inhibits pyruvate dehydrogenase, thereby promoting the Warburg effect in HCC by metabolically switching from oxidative phosphorylation to aerobic glycolysis under normoxic conditions5,6. Potential therapeutic strategies include treating with let-7 mimetics or Lin28 inhibitors to increase the tumor suppressor role of let-7 and decrease ATP production in HCC cells.
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