Sonia Rao

 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 treatments^1,2. 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 understood^3,4,5. 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 conditions^5,6. 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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