The miR-873/NDFIP1 axis promotes hepatocellular carcinoma growth and metastasis through the AKT/mTOR-mediated Warburg effect

[摘要] Hepatocellular carcinoma (HCC) progression depends on cellular metabolic reprogramming as both direct and indirect consequence of oncogenic lesions. However, the underlying mechanisms are still understood poorly. Here, we report that miR-873 promotes Warburg effect in HCC cells by increasing glucose uptake, extracellular acidification rate (ECAR), lactate production, and ATP generation, and decreasing oxygen consumption rate (OCR) in HCC cells. Mechanistically, we show that miR-873 activates the key glycolytic proteins AKT/mTOR via targeting NDFIP1 which triggers metabolic shift. We further demonstrate that enhanced glycolysis is essential for the role of miR-873 to drive HCC progression. By using immunohistochemistry analysis, we show a link between the aberrant expression of miR-873, NDFIP1, and phospho-AKT in clinical HCC samples. We also found that miR-873 was up-regulated by HIF1α, a critical glycolysis-related transcription factor. However, BAY 87-2243, a HIF1α specific inhibitor, blocks miR-873 mediated tumor growth and metastasis in nude mice. Collectively, our data uncover a previously unappreciated function of miR-873 in HCC cell metabolism and tumorigenesis, suggesting that targeting miR-873/NDFIP1 axis could be a potential therapeutic strategy for the treatment of HCC patients.

[学科分类] 肿瘤学

[关键词] miR-873;NDFIP1;HCC;Warburg effect