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

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.

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Mechanism, Clinical Significance, and Treatment Strategy of Warburg Effect in Hepatocellular Carcinoma

Journal of Nanomaterials ◽

10.1155/2021/5164100 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Hui Chen ◽

Qing Wu ◽

Liu Peng ◽

Ting Cao ◽

Man-Ling Deng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Oxidative Phosphorylation ◽

Tumor Cells ◽

Clinical Significance ◽

Warburg Effect ◽

Noncoding Rna ◽

Immune Escape ◽

Migration And Invasion ◽

Hcc Cells ◽

The Warburg Effect

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and the third leading cause of cancer death worldwide. The incidence of HCC accounts for more than 90% of primary HCC. Like most solid malignancies, the occurrence and development of HCC are closely related to the Warburg effect. The Warburg effect of HCC is mainly manifested as increased glucose uptake by HCC cells, increased glycolysis, restricted mitochondrial oxidative phosphorylation, increased pentose phosphate pathway in HCC cells, and increased glutamine decomposition. As the contribution of glycolysis to the total ATP of tumor cells generally does not exceed 50% to 60%, oxidative phosphorylation (OXPHOS) still makes a considerable contribution to the ATP of tumor cells. In some cases, there will be an anti-Warburg effect. HCC Warburg effect is closely related to HCC cell proliferation, apoptosis, immune escape, migration and invasion, chemotherapy resistance, and treatment failure. The mechanism of the Warburg effect in HCC is complex, involving the expression of stimulating the key glycolysis enzymes by hypoxia-inducible factor-1(HIF-1), the activation of oncogenes and the inactivation of tumor suppressor genes, the continuous activation of related signaling pathways, the participation of noncoding RNA, and the rate of metabolism gene mutation of enzyme. This article synthetically discusses the characteristics of glucose metabolism in HCC cells, the mechanism of Warburg effect, clinical significance, and corresponding treatment strategies and provides new perspectives for the prevention and treatment of HCC.

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Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

Acta Pharmacologica Sinica ◽

10.1038/aps.2016.47 ◽

2016 ◽

Vol 37 (8) ◽

pp. 1013-1019 ◽

Cited By ~ 27

Author(s):

Xi-sha Chen ◽

Lan-ya Li ◽

Yi-di Guan ◽

Jin-ming Yang ◽

Yan Cheng

Keyword(s):

Tumor Cells ◽

Warburg Effect ◽

Metabolic Profile ◽

Therapeutic Targeting ◽

The Warburg Effect

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microRNA-129-5p, a c-Myc negative target, affects hepatocellular carcinoma progression by blocking the Warburg effect

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjw010 ◽

2016 ◽

Vol 8 (5) ◽

pp. 400-410 ◽

Cited By ~ 27

Author(s):

Han Han ◽

Wenjuan Li ◽

Hongxing Shen ◽

Jinxiang Zhang ◽

Yahui Zhu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Warburg Effect ◽

Negative Target ◽

The Warburg Effect

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LncRNA IDH1-AS1 links the functions of c-Myc and HIF1α via IDH1 to regulate the Warburg effect

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1711257115 ◽

2018 ◽

Vol 115 (7) ◽

pp. E1465-E1474 ◽

Cited By ~ 35

Author(s):

Shaoxun Xiang ◽

Hao Gu ◽

Lei Jin ◽

Rick F. Thorne ◽

Xu Dong Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Enzymatic Activity ◽

Cancer Cells ◽

Long Noncoding Rna ◽

Warburg Effect ◽

Noncoding Rna ◽

Ros Production ◽

Xenograft Growth ◽

The Relationship ◽

The Warburg Effect

The oncoprotein c-Myc plays an important role in regulating glycolysis under normoxia; yet, in cancer cells, HIF1α, which is essential for driving glycolysis under hypoxia, is often up-regulated even in the presence of oxygen. The relationship between these two major regulators of the Warburg effect remains to be fully defined. Here we demonstrate that regulation of a long noncoding RNA (lncRNA), named IDH1-AS1, enables c-Myc to collaborate with HIF1α in activating the Warburg effect under normoxia. c-Myc transcriptionally repressed IDH1-AS1, which, upon expression, promoted homodimerization of IDH1 and thus enhanced its enzymatic activity. This resulted in increased α-KG and decreased ROS production and subsequent HIF1α down-regulation, leading to attenuation of glycolysis. Hence, c-Myc repression of IDH1-AS1 promotes activation of the Warburg effect by HIF1α. As such, IDH1-AS1 overexpression inhibited cell proliferation, whereas silencing of IDH1-AS1 promoted cell proliferation and cancer xenograft growth. Restoring IDH1-AS1 expression may therefore represent a potential metabolic approach for cancer treatment.

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