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Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma.

ABSTRACT: Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75-85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of aerobic glycolysis and other molecular mechanisms. Aerobic glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible for the regulation of proliferation, immune evasion, invasion, metastasis, angiogenesis, and drug resistance in HCC. The three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinases type M2 (PKM2) play an important role in the regulation of aerobic glycolysis in HCC and can be regulated by many mechanisms, such as the AMPK, PI3K/Akt pathway, HIF-1?, c-Myc and noncoding RNAs. Because of the importance of aerobic glycolysis in the progression of HCC, targeting key factors in its pathway such as the inhibition of HK2, PFK or PKM2, represent potential new therapeutic approaches for the treatment of HCC.

SUBMITTER: Feng J

PROVIDER: S-EPMC7336654 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma.

Feng Jiao J Li Jingjing J Wu Liwei L Yu Qiang Q Ji Jie J Wu Jianye J Dai Weiqi W Guo Chuanyong C

Journal of experimental & clinical cancer research : CR 20200706 1

Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75-85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of aerobic glycolysis and other molecular mechanisms. Aerobic glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible ...[more]

PMID: 32631382

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Project description:BackgroundThe shortening of 3' untranslated regions (3'UTRs) of messenger RNAs(mRNAs) by alternative polyadenylation (APA) is an important mechanism for oncogene activation. Cleavage stimulation factor 2 (CSTF2), an important regulator of APA, has been reported to have a tumorigenic function in urothelial carcinoma of the bladder and lung cancers. However, the tumor-promoting role of CSTF2 in hepatocellular carcinoma (HCC) and its underlying molecular mechanism remains unclear.MethodsMultiple databases were used to analyze the expression level and prognostic value of CSTF2 in HCC. Function enrichment analysis was used to investigate the molecular mechanism of CSTF2 for the occurrence and development of HCC. The biological function in HCC cell lines in vitro was determined by CCK8, colony formation, Transwell migration, and invasion assay. Moreover, the tumorigenic function of CSTF2 in vivo was measured by a subcutaneous tumor formation or injecting four plasmids into a mouse tail vein within 5-7 s in an immunocompetent HCC mouse model. In addition, aerobic glycolysis in HCC cells was determined by measuring the extracellular acid rate (ECAR) and extracellular glucose and lactate levels.ResultsBioinformatics analysis revealed that CSTF2 was overexpressed in HCC tissues. The high expression of CSTF2 was correlated with a poor prognosis and high histological grades. CSTF2 knockout inhibited the proliferation, migration, and invasion of HCC cells. In addition, CSTF2 knockout HCC cells failed to form tumors by a subcutaneous graft experiment. Furthermore, endogenous CSTF2 knockout attenuated hepatocarcinogenesis in an immunocompetent HCC mouse model. Function enrichment analysis suggested that the high expression of CSTF2 was associated with enhanced glycolysis. Moreover, we found that CSTF2 knockout reduced the level of the short 3' UTR isoform of hexokinase 2 and increased its level of long 3'UTR. Furthermore, CSTF2 knockout inhibited ECAR levels, glucose uptake, and lactate production.ConclusionOur results indicated that CSTF2 is highly expressed in HCC and is correlated with a poor prognosis and high histological grade. The knockout of CSTF2 inhibits the tumorigenesis and procession of HCC both in vitro and in vivo. Moreover, CSTF2 is associated with enhanced glycolysis. Therefore, this study suggests that CSTF2 might be a new prognostic biomarker and therapeutic target for HCC.

Project description:Background: Hepatocellular Carcinoma (HCC) is a major form of liver cancer and a leading cause of cancer-related death worldwide. New insights into HCC pathobiology and mechanism of drug actions are urgently needed to improve patient outcomes. HCC undergoes metabolic reprogramming of glucose metabolism from respiration to aerobic glycolysis, a phenomenon known as the 'Warburg Effect' that supports rapid cancer cell growth, survival, and invasion. mTOR is known to promote Warburg Effect, but the underlying mechanism(s) remains poorly defined. The aim of this study is to understand the mechanism(s) and significance of mTOR regulation of aerobic glycolysis in HCC. Methods: We profiled mTORC1-dependent long non-coding RNAs (lncRNAs) by RNA-seq of HCC cells treated with rapamycin. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the transcriptional regulation of NEAT1 by mTORC1. [U-13C]-glucose labeling and metabolomic analysis, extracellular acidification Rate (ECAR) by Seahorse XF Analyzer, and glucose uptake assay were used to investigate the role of mTOR-NEAT1-NONO signaling in the regulation of aerobic glycolysis. RNA immunoprecipitation (RIP) and NONO-binding motif scanning were performed to identify the regulatory mechanism of pre-mRNA splicing by mTOR-NEAT1. Myristoylated AKT1 (mAKT1)/NRASV12-driven HCC model developed by hydrodynamic transfection (HDT) was employed to explore the significance of mTOR-NEAT1 signaling in HCC tumorigenesis and mTOR-targeted therapy. Results: mTOR regulates lncRNA transcriptome in HCC and that NEAT1 is a major mTOR transcriptional target. Interestingly, although both NEAT1_1 and NEAT1_2 are down-regulated in HCC, only NEAT1_2 is significantly correlated with poor overall survival of HCC patients. NEAT1_2 is the organizer of nuclear paraspeckles that sequester the RNA-binding proteins NONO and SFPQ. We show that upon oncogenic activation, mTORC1 suppresses NEAT1_2 expression and paraspeckle biogenesis, liberating NONO/SFPQ, which in turn, binds to U5 within the spliceosome, stimulating mRNA splicing and expression of key glycolytic enzymes. This series of actions lead to enhanced glucose transport, aerobic glycolytic flux, lactate production, and HCC growth both in vitro and in vivo. Furthermore, the paraspeckle-mediated mechanism is important for the anticancer action of US FDA-approved drugs rapamycin/temsirolimus. Conclusions: These findings reveal a molecular mechanism by which mTOR promotes the 'Warburg Effect', which is important for the metabolism and development of HCC, and anticancer response of mTOR-targeted therapy.

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Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma.

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Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma.

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