lncENST Suppress the Warburg Effect Regulating the Tumor Progress by the Nkx2-5/ErbB2 Axis in Hepatocellular Carcinoma

Abstract

The therapeutic efficacy of radiofrequency ablation (RFA) against liver cancer is often limited by proliferation and metastasis of residual tumor cells. These phenomena are closely associated with the Warburg effect, wherein ErbB2 is activated. While RFA inhibits the Warburg effect of residual tumor cells at the early stage, the specific mechanisms remain unclear. We explored the regulatory relationship between the long noncoding RNA ENST00000570843.1 (lncENST) and ErbB2 using lentiviral transfection of lncENST and ErbB2 overexpression/interference vectors in in vitro and in vivo models of hepatocellular carcinoma in the presence of sublethal heat at 50°C. ErbB2-mediated Warburg effect was suppressed by lncENST, as manifested by reduced glucose uptake and lactic acid production in SMMC-7721 cells. lncENST also increased tumor apoptosis and inhibited tumor progression in nude Balb/c mice for up to 28 days after RFA. Additionally, we predicted through bioinformatic analysis that the promoter of ErbB2 binds to the transcription factor Nkx2-5, resulting in a negative regulatory effect. This speculation was confirmed by chromatin immunoprecipitation of the Nkx2-5 protein and ErbB2, indicating that ErbB2 transcription was curbed by Nkx2-5. We propose that lncENST downplays the Warburg effect in residual tumor cells by downregulating ErbB2 via Nkx2-5 activation. This study is aimed at providing molecular targets that can prevent residual tumor cell proliferation after RFA, with clinical significance in hepatocellular carcinoma treatment.

Long noncoding RNAs, glucose metabolism and cancer (Review)

“…Inhibiting the Warburg effect in HCC cells, lncENST directly binds to and activates the transcription factor Nkx2-5 through an Nkx2-5/ErbB2 axis. This inhibits ErbB2 gene transcription and downregulates ErbB2 protein expression (38). HOX transcript antisense RNA (HOTAIR) regulates a miR-130a-3p/HIF1A axis on miR-130a-3p uptake, resulting in high expression of HIF1A, which inhibits glycolysis in hypoxia-induced HCC cells (63).…”

“…1, it was found that lncRNAs, including protein tyrosine phosphatase receptor type G antisense RNA 1 (PTPRG-AS1) (31), H19 (32), MIR210 host gene (MIR210HG) (33), MIR17HG (29), LINC00243 (34), and LINC00346 (35), promote the growth of tumor cells, altering the expression of key gluconeogenesis enzymes through sponging of miRNAs. Additionally, several signaling molecules are regulated by lncRNAs, such as transmembrane protein 161B antisense RNA 1 (TMEM161B-AS1) (36), high expression in hepatocellular carcinoma (HEIH) (37), lncENST (38), and LINC00261 (28), that can affect glycolysis and tumor cell activity (Fig. 2).…”

Retracted: lncENST Suppress the Warburg Effect Regulating the Tumor Progress by the Nkx2‐5/ErbB2 Axis in Hepatocellular Carcinoma

“…This article has been retracted by Hindawi, as publisher, following an investigation undertaken by the publisher [ 1 ]. This investigation has uncovered evidence of systematic manipulation of the publication and peer-review process.…”