Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs’ roles in HCC and to determine the most effective ways to translate these findings into clinical practice.

• Hepatocellular carcinoma
• Glucose transporter protein
• Metabolic reprogramming
• Therapeutic target
• Drug resistance

• gluconeogenesis
• glucose metabolism
• glycolytic pathway
• hepatocellular carcinoma (HCC)
• metabolic reprogramming
• pentose phosphate pathway (PPP)
• tricarboxylic acid cycle (TCA)

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Thrombospondin 1/genetics
• Thrombospondin 1/metabolism
• Transforming Growth Factor beta1/metabolism
• Pulmonary Fibrosis/genetics
• Pulmonary Fibrosis/metabolism
• Pulmonary Fibrosis/chemically induced
• Pulmonary Fibrosis/pathology
• Animals
• Humans
• Mice
• Epithelial-Mesenchymal Transition/genetics
• Signal Transduction
• Male
• 3' Untranslated Regions
• Cell Line
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Epithelial Cells/drug effects

• National Research Foundation of Korea
• National Institute of Biological Resources

• delivery systems
• drug resistance
• hepatocellular carcinoma
• microRNAs
• targeted therapy
• tumor heterogeneity

• Humans
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/genetics
• Liver Neoplasms/therapy
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Gene Expression Regulation, Neoplastic
• Animals
• Biomarkers, Tumor/genetics

• aerobic glycolysis
• glycolytic modulators
• post-translational modification
• targeted cancer therapy
• transcriptional regulation

• Humans
• Protein Processing, Post-Translational
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/genetics
• Glycolysis/drug effects
• Animals
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Transcription, Genetic
• Molecular Targeted Therapy/methods
• Gene Expression Regulation, Neoplastic

• IGF-1R
• epithelial–mesenchymal transition
• interleukin-6
• miR-455-5p
• pancreatic cancer

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Interleukin-6/metabolism
• Interleukin-6/genetics
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Receptor, IGF Type 1/metabolism
• Receptor, IGF Type 1/genetics
• Cell Proliferation
• Mice
• Cell Line, Tumor
• Neoplasm Metastasis
• Animals
• Gene Expression Regulation, Neoplastic
• Male
• Epithelial-Mesenchymal Transition/genetics
• Female

• IGF1R
• Multiple myeloma
• circ_0005615
• miR-331-3p

• Angiogenesis
• GLUT proteins
• Glioblastoma
• Glucose metabolism
• HIF-1α
• miRNAs

• fructose and pentose phosphate metabolism
• galactose metabolism
• hepatocellular carcinoma
• schisantherin A
• traditional Chinese medicine

• National Natural Science Foundation of China
• Ministry of Education
• Natural Science Foundation of Chongqing

• GLUT
• glutor
• neoplastic cells
• pan-GLUT inhibitors
• tumor metabolism

Background: N⁶ methyladenosine (m⁶A)-related noncoding RNAs (including lncRNAs and miRNAs) are closely related to the development of cancer. However, the gene signature and prognostic value of m⁶A regulators and m⁶A-associated RNAs in regulating sarcoma (SARC) development and progression remain largely unexplored. Therefore, further research is required.

Methods: We obtained expression data for RNA sequencing (RNA-seq) and miRNAs of SARC from The Cancer Genome Atlas (TCGA) datasets. Correlation analysis and two target gene prediction databases (miRTarBase and LncBase v.2) were used to deduce m⁶A-related miRNAs and lncRNAs, and Cytoscape software was used to construct ceRNA-regulating networks. Based on univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, an m⁶A-associated RNA risk signature (m6Ascore) model was established. Prognostic differences between subgroups were explored using Kaplan–Meier (KM) analysis. Risk score-related biological phenotypes were analyzed in terms of functional enrichment, tumor immune signature, and tumor mutation signature. Finally, potential immunotherapy features and drug sensitivity predictions for this model were also discussed.

Results: A total of 16 miRNAs, 104 lncRNAs, and 11 mRNAs were incorporated into the ceRNA network. The risk score was obtained based on RP11-283I3.6, hsa-miR-455-3p, and CBLL1. Patients were divided into two risk groups using the risk score, with patients in the low-risk group having longer overall survival (OS) than those in the high-risk group. The receiver operating characteristic (ROC) curves indicated that risk characteristic performed well in predicting the prognosis of patients with SARC. In addition, lower m6Ascore was also positively correlated with the abundance of immune cells such as monocytes and mast cells activated, and several immune checkpoint genes were highly expressed in the low-m6Ascore group. According to our analysis, lower m6Ascore may lead to better immunotherapy response and OS outcomes. The risk signature was significantly associated with the chemosensitivity of SARC. Finally, a nomogram was constructed to predict the OS in patients with SARC. The concordance index (C-index) for the nomogram was 0.744 (95% CI: 0.707–0.784). The decision curve analysis (DCA), calibration plot, and ROC curve all showed that this nomogram had good predictive performance.

Conclusion: This m6Ascore risk model based on m⁶A RNA methylation regulator-related RNAs may be promising for clinical prediction of prognosis and might contain potential biomarkers for treatment response prediction for SARC patients.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Metabolic reprogramming is considered to be an important hallmark of cancer. Emerging studies have demonstrated that noncoding RNAs (ncRNAs) are closely associated with metabolic reprogramming of HCC. NcRNAs can directly regulate the expressions or functions of metabolic enzymes or indirectly regulate the metabolism of HCC cells through some vital signaling pathways. Until now, the mechanisms of HCC development and progression remain largely unclear, and understanding the regulatory mechanism of ncRNAs on metabolic reprogramming of HCC may provide an important basis for breakthrough progress in the treatment of HCC. In this review, we summarize the ncRNAs involved in regulating metabolic reprogramming of HCC. Specifically, the regulatory roles of ncRNAs in glucose, lipid and amino acid metabolism are elaborated. In addition, we discuss the molecular mechanism of ncRNAs in regulation of metabolic reprogramming and possible therapeutic strategies that target the metabolism of cancer cells by modulating the expressions of specific ncRNAs.

• CircRNA
• Hepatocellular carcinoma
• LncRNA
• Metabolic Reprogramming
• Non-coding RNA

The present study aimed at investigating the effects and mechanism of long noncoding RNA highly upregulated in metastatic triple-negative breast cancer lymph node (lncRNA HUMT) in hepatocellular carcinoma (HCC). Quantitative real-time polymerase chain reaction was used to assess the expression of HUMT, microRNA (miR)-455-5p, and low-density lipoprotein receptor-related protein 4 (LRP4) in HCC tissues. Colony forming and 5-ethynyl-2′-deoxyuridine assays were performed to assess cell proliferation. Transwell assay was performed to measure cell migration and invasion. Cell cycle distribution was assessed using flow cytometry. The protein expression of LRP4, proliferating cell nuclear antigen (PCNA), matrix metallopeptidase 2 (MMP-2), and MMP-9 was detected using western blot. Luciferase reporter assay and RNA immunoprecipitation assay was used to confirm the target association between miR-455-5p and HUMT or LRP4. In our study, the level of HUMT was enhanced in HCC tissues and cells. Cell proliferation, invasion, and migration in HCC cells were repressed by knockdown of HUMT, and knockdown of HUMT arrested cells in G1 phase and decreased the levels of PCNA, MMP-2, and MMP-9. MiR-455-5p was a target of HUMT. Lowexpression of miR-455-5p reversed the inhibitive influence on HCC cells induced by of HUMT silencing. LRP4 was a target of miR-455-5p and was negatively regulated by miR-455-5p. In addition, LRP4 expression was positively modified by HUMT, and LRP4 inhibited the inhibitory effects on HCC cells induced by HUMT silencing. In conclusion, HCC cell proliferation, invasion, and migration were restrained by knockdown of HUMT, which was related to the miR-455-5p/LRP4 axis.

• LRP4
• hepatic cancer
• lncRNA HUMT
• miR-455-5p

Previous research indicates that hypoxia critically affects the initiation and progression of hepatocellular carcinoma (HCC). Nevertheless, the molecular mechanisms responsible for HCC development are poorly understood. Herein, we purposed to build a prognostic model using hypoxia-linked genes to predict patient prognosis and investigate the relationship of hypoxia with immune status in the tumor microenvironment (TME).

The training cohort included transcriptome along with clinical data abstracted from The Cancer Genome Atlas (TCGA). The validation cohort was abstracted from Gene Expression Omnibus (GEO). Univariate along with multivariate Cox regression were adopted to create the prediction model. We divided all patients into low- and high-risk groups using median risk scores. The estimation power of the prediction model was determined with bioinformatic tools.

Six hypoxia-linked genes, HMOX1, TKTL1, TPI1, ENO2, LDHA, and SLC2A1, were employed to create an estimation model. Kaplan-Meier, ROC curve, and risk plot analyses demonstrated that the estimation potential of the risk model was satisfactory. Univariate along with multivariate regression data illustrated that the risk model could independently predict the overall survival (OS). A nomogram integrating the risk signature and clinicopathological characteristics showed a good potential to estimate HCC prognosis. Gene set enrichment analysis (GSEA) revealed that genes associated with cell proliferation and metabolism cascades were abundant in high-risk group. Furthermore, the signature showed a strong ability to distinguish the two groups in terms of immune status.

A prediction model for predicting HCC prognosis using six hypoxia-linked genes was designed in this study, facilitating the diagnosis and treatment of HCC.

• Hepatocellular carcinoma (HCC)
• The Cancer Genome Atlas (TCGA)
• hypoxia
• prognosis
• survival

Ischemic stroke (IS) is an essential contributor to the neurological morbidity and mortality throughout the world. The significance of circular RNA tousled-like kinase 1 (circTLK1) in IS has been documented. This study set out to explore the mechanism of circTLK1 in IS. Middle cerebral artery occlusion (MCAO) mouse models in vivo and oxygen-glucose deprivation and reoxygenation (OGD/R) cell models in vitro were first established, followed by evaluation of infarct volume and neurological impairment, and cell viability and apoptosis. The expression patterns of circTLK1, miR-26a-5p, phosphatase and tensin homolog (PTEN), insulin-like growth factor type 1 receptor (IGF-1 R), and glucose transporter type 1 (GLUT1) were detected by RT-qPCR and Western blotting. Co-localization of circTLK1 and miR-26a-5p in N2a cells was tested by fluorescence in situ hybridization assay. The binding relationships among circTLK1, PTEN, and miR-26a-5p were verified by dual-luciferase assay and RNA pull-down. circTLK1 and PTEN were highly expressed while miR-26a-5p was under-expressed in IS models. circTLK1 knockdown decreased infarct volume and neurological impairment in MCAO mouse models and relieved OGD/R-induced neuronal injury in vitro. circTLK1 and miR-26a-5p were co-located in the N2a cell cytoplasm. circTLK1 regulated PTEN as a sponge of miR-26a-5p. PTEN positively regulated IGF-1 R and GLUT1 expressions. miR-26a-5p inhibitor annulled the repressive effects of circTLK1 silencing on OGD/R-induced neuronal injury. sh-PTEN partially annulled the effects of the miR-26a-5p inhibitor on OGD/R-induced neuronal injury. In conclusion, circTLK1 knockdown relieved IS via the miR-26a-5p/PTEN/IGF-1 R/GLUT1 axis. These results may provide a new direction to IS potential therapeutic targets.

Neuroinflammation is a major pathophysiological factor that results in the development of brain injury after cerebral ischemia/reperfusion. Downregulation of microRNA (miR)-455-5p after ischemic stroke has been considered a potential biomarker and therapeutic target for neuronal injury after ischemia. However, the role of miR-455-5p in the post-ischemia/reperfusion inflammatory response and the underlying mechanism have not been evaluated. In this study, mouse models of cerebral ischemia/reperfusion injury were established by transient occlusion of the middle cerebral artery for 1 hour followed by reperfusion. Agomir-455-5p, antagomir-455-5p, and their negative controls were injected intracerebroventricularly 2 hours before or 0 and 1 hour after middle cerebral artery occlusion (MCAO). The results showed that cerebral ischemia/reperfusion decreased miR-455-5p expression in the brain tissue and the peripheral blood. Agomir-455-5p pretreatment increased miR-455-5p expression in the brain tissue, reduced the cerebral infarct volume, and improved neurological function. Furthermore, primary cultured microglia were exposed to oxygen-glucose deprivation for 3 hours followed by 21 hours of reoxygenation to mimic cerebral ischemia/reperfusion. miR-455-5p reduced C-C chemokine receptor type 5 mRNA and protein levels, inhibited microglia activation, and reduced the production of the inflammatory factors tumor necrosis factor-α and interleukin-1β. These results suggest that miR-455-5p is a potential biomarker and therapeutic target for the treatment of cerebral ischemia/reperfusion injury and that it alleviates cerebral ischemia/reperfusion injury by inhibiting C-C chemokine receptor type 5 expression and reducing the neuroinflammatory response.

• C-C chemokine receptor type 5
• agomiR-455-5p
• biomarker
• blood-brain barrier
• ischemia/reperfusion injury
• ischemic stroke
• microRNA-455-5p
• microglia
• neuroinflammation
• pretreatment

• histone lysine lactylation
• immunosuppression
• lactate
• metabolic reprogramming
• the Warburg effect

• Carcinoma, Hepatocellular
• Glycolysis
• Humans
• Immunosuppression Therapy
• Lactic Acid/metabolism
• Liver Neoplasms
• Tumor Microenvironment

• National Key Research and Development Program of China

BAY-876 is an effective antagonist of the Glucose transporter type 1 (GLUT1) receptor, a mediator of aerobic glycolysis, a biological process considered a hallmark of hepatocellular carcinoma (HCC) together with cell proliferation, drug-resistance, and metastasis. However, the clinical application of BAY-876 has faced many challenges. In the presence study, we describe the formulation of a novel microcrystalline BAY-876 formulation. A series of HCC tumor models were established to determine not only the sustained release of microcrystalline BAY-876, but also its long-acting antitumor activity. The clinical role of BAY-876 was confirmed by the increased expression of GLUT1, which was associated with the worse prognosis among advanced HCC patients. A single dose of injection of microcrystalline BAY-876 directly in the HCC tissue achieved sustained localized levels of Bay-876. Moreover, the single injection of microcrystalline BAY-876 in HCC tissues not only inhibited glucose uptake and prolonged proliferation of HCC cells, but also inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors. Thus, the microcrystalline BAY-876 described in this study can directly achieve promising localized effects, given its limited diffusion to other tissues, thereby reducing the occurrence of potential side effects, and providing an additional option for advanced HCC treatment.

• BAY-876
• advanced hepatocellular carcinoma
• aerobic glycolysis
• epithelial-mesenchymal transition
• glucose transporter type 1
• microcrystalline

Imatinib mesylate (imatinib) is the primary agent of choice used to treat gastrointestinal stromal tumors (GIST). However, drug resistance to imatinib poses a major obstacle to treatment efficacy. In addition, the relationship between imatinib resistance and glycolysis is poorly understood. Glucose transporter (GLUT)-1 is a key component of glycolysis. The present study aimed to assess the potential relationship between components in the glycolytic pathway and the acquisition of imatinib resistance by GIST cells, with particular focus on GLUT-1. An imatinib-resistant GIST cell line was established through the gradual and continuous imatinib treatment of the parental human GIST cell line GIST-T1. The expression of glycolysis-related molecules (GLUT-1, hexokinase 2, pyruvate kinase M2 and lactate dehydrogenase) was assessed in parental and imatinib-resistant cells by western blotting, reverse transcription-quantitative PCR and glucose and lactate measurement kits. In addition, clinical information and transcriptomic data obtained from the gene expression omnibus database (GSE15966) were used to confirm the in vitro results. The potential effects of GLUT-1 inhibition on the expression of proteins in the glycolysis (GLUT-1, hexokinase 2, pyruvate kinase M2 and lactate dehydrogenase) and apoptosis pathways (Bcl-2, cleaved PARP, caspase-3 and caspase-9) in imatinib-resistant cells were then investigated following gene silencing and treatment using the GLUT-1 inhibitor WZB117 by western blotting. For gene silencing, the mature siRNAs for SLC2A1 were used for cell transfection. Annexin V-FITC/PI double-staining followed by flow cytometry was used to measure apoptosis whereas three-dimensional culture experiments were used to create three-dimensional spheroid cells where cell viability and spheroid diameter were measured. Although imatinib treatment downregulated GLUT-1 expression and other glycolysis pathway components hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase in parental GIST-T1 cells even at low concentrations. By contrast, expression of these glycolysis pathway components in imatinib-resistant cells were increased by imatinib treatment. WZB117 administration significantly downregulated AKT phosphorylation and Bcl-2 expression in imatinib-resistant cells, whereas the combined administration of imatinib and WZB117 conferred synergistic growth inhibition effects in apoptosis assay. WZB117 was found to exert additional inhibitory effects by inducing apoptosis in imatinib-resistant cells. Therefore, the present study suggests that GLUT-1 is involved in the acquisition of imatinib resistance by GIST cells, which can be overcome by combined treatment with WZB117 and imatinib.

• WZB117
• Warburg effect
• gastrointestinal stromal tumor
• glucose transporter‑1
• imatinib

• Adh6-ps1
• gene expression
• gene interaction
• pseudogene

• bioinformatics analysis
• differentially expressed genes
• differentially expressed microRNAs
• hsa-miR-455-3p
• pancreatic adenocarcinoma

• CXCL12/CXCR4 signaling pathway
• Medullary thyroid cancer
• circPVT1
• miR-455-5p

• Animals
• Carcinoma, Neuroendocrine/genetics
• Carcinoma, Neuroendocrine/metabolism
• Carcinoma, Neuroendocrine/pathology
• Cell Line, Tumor
• Chemokine CXCL12/genetics
• Chemokine CXCL12/metabolism
• Heterografts
• Humans
• Mice
• Mice, Nude
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasm Metastasis
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Signal Transduction
• Thyroid Neoplasms/genetics
• Thyroid Neoplasms/metabolism
• Thyroid Neoplasms/pathology
• Transfection

• IGF
• disorders
• expression
• lncRNA
• miRNA

• PARVA
• TSCC
• circCLK3
• miR-455-5p
• progression

• LUC7L3
• MiR-370-5p
• breast cancer
• invasion
• proliferation

• atherosclerosis
• lncRNA HOXA-AS3
• miR-455-5p
• p27 Kip1

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-1α, 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.

• Aerobic glycolysis
• HIF-1α
• HK2
• Hepatocellular carcinoma
• PFK1
• PKM2

• AKT
• GLUT1
• S6K1
• gastric cancer

Hepatocellular carcinoma (HCC) is one of the most common global malignancies with increasing morbidity and mortality. The purpose of this study was to investigate the expression levels and prognostic value of microRNA-3607 (miR-3607) in patients with HCC.

The expression of miR-3607 was estimated by quantitative real-time RT-PCR. Survival analysis using the Kaplan-Meier method and Cox regression analysis was conducted to evaluate the prognostic value of miR-3607. The functional role of miR-3607 in HCC progression was further assessed using gain- and loss-of-function experiments. Bioinformatics analysis and a dual-luciferase reporter assay were used to explore the direct targets of miR-3607.

miR-3607 expression was found to be significantly decreased in HCC tissues and cells compared with the matched tissues and cells (P < 0.001). The decreased expression of miR-3607 was associated with the patients’ tumor size and TNM stage (all P < 0.05). According to the survival curves, patients with low miR-3607 expression had poorer overall survival than those with high levels (log-rank P = 0.012). Moreover, the Cox analysis results indicated that miR-3607 expression was an independent prognostic factor for HCC. The results of cell experiments revealed that the overexpression of miR-3607 in HCC cells led to the inhibited cell proliferation, migration, and invasion. TGFBR1 was identified as a direct target of miR-3607.

The data of this study indicated that the decreased expression of miR-3607 in HCC predicts poor prognosis and the overexpression of miR-3607 in HCC cells can suppress the tumor progression by targeting TGFBR1. This study provides a novel insight into the prognosis and treatment of HCC, and miR-3607 serves as a candidate prognostic biomarker and therapeutic target of HCC.

• Hepatocellular carcinoma
• MicroRNA-3607
• Prognosis
• Tumor progression