Long noncoding RNA FIRRE contributes to the proliferation and glycolysis of hepatocellular carcinoma cells by enhancing PFKFB4 expression

Abstract

Recent reports show that long noncoding RNA (lncRNA) FIRRE contributes to the proliferation, apoptosis resistance, and invasion of colorectal cancer and diffuse large B-cell lymphoma. However, the biological function of FIRRE in hepatocellular carcinoma (HCC) remains unknown. Here, we disclosed that the FIRRE level was frequently increased in HCC compared to nontumor tissues. Compared with normal liver cells, we also confirmed the upregulated level of FIRRE in HCC cells. Notably, the FIRRE high expression was related to malignant clinical features, including advanced TNM stage and tumor size ≥5 cm, and conferred to worse survival of HCC. Functionally, FIRRE knockdown repressed the proliferation and glycolysis of HCCLM3 cells. Overexpression of FIRRE strengthened Huh7 cell proliferation and glycolysis. Notably, FIRRE positively regulated the glycolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) expression in HCC cells. PFKFB4 was highly expressed and positively associated with FIRRE level in HCC tissues. The upregulated expression of PFKFB4 was associated with high tumor grade and advanced TNM stage. TCGA data revealed that the PFKFB4 high expression indicated a poor prognosis of HCC. Mechanistically, modulating FIRRE level did not affect the stability of PFKFB4 mRNA. FIRRE was mainly distributed in HCC cells' nucleus and promoted PFKFB4 transcription and expression via cAMP-responsive element-binding protein (CREB). PFKFB4 could abolish the effects of FIRRE knockdown on HCC cell proliferation and glycolysis. To conclude, the highly expressed FIRRE facilitated HCC cell proliferation and glycolysis by enhancing CREB-mediated PFKFB4 transcription and expression.