HIF1A activates the transcription of lncRNA RAET1K to modulate hypoxia-induced glycolysis in hepatocellular carcinoma cells via miR-100-5p.

Hepatocellular carcinoma (HCC) remains the primary cause of cancer-related death. Metabolic change is the major characteristic of cancer. The present study attempted to investigate the regulatory mechanisms of HCC energy metabolism from the perspective of noncoding RNA regulation of HIF1A and LDHA. The expression of miR-100-5p expression was significantly suppressed in HCC tissue samples and HCC cell lines under 1% O2-induced hypoxia. miR-100-5p overexpression significantly suppressed hypoxia-induced increases in lactate concentration and glucose uptake. Exposure to 1% O2 induced HIF1A protein and reduced miR-100-5p expression, while HIF1A silencing dramatically rescued miR-100-5p expression upon 1% O2 exposure. In addition, 1% O2-induced increases in lactate concentration and glucose uptake were also suppressed by HIF1A silencing. Next, by analyzing available data in TCGA, we found that lncRNA RAET1K was correlated with HIF1A and miR-100-5p.LncRNA RAET1K could downregulate the expression of miR-100-5p by acting as a sponge, while HIF1A bound the lncRNA RAET1K promoter region to activate its transcription. LncRNA RAET1K silencing significantly suppressed HCC cell proliferation and invasion and also suppressed hypoxia-induced increases in lactate concentration and glucose uptake, while miR-100-5p inhibition reversed the effects of lncRNA RAET1K silencing on hypoxia-induced glycolysis in HCC cells. Finally, the expression of HIF1A, lncRNA RAET1K, and LDHA was upregulated in HCC tissue specimens; the expression of miR-100-5p was negatively related to HIF1A, lncRNA RAET1K, and LDHA; and HIF1A, lncRNA RAET1K, and LDHA were positively correlated with each other. In conclusion, the HIF1A/lncRNA RAET1K/miR-100-5p axis modulates hypoxia-induced glycolysis in HCC cells and might affect HCC progression.

Pubmed ID: 32152275