Aerobic glycolysis is a phenomenon by which malignant cells preferentially metabolize glucose through the glycolytic pathway, rather than oxidative phosphorylation to proliferate efficiently. The present study aimed to investigate the expression and functional implications of long non-coding (lnc)RNA Ftx in the aerobic glycolysis and tumorigenesis of hepatocellular carcinoma (HCC). It was identified that lncRNA Ftx was upregulated in human HCC tissues and cell lines and, notably, was associated with aggressive clinicopathological features. lncRNA Ftx overexpression promoted the proliferation, invasion and migration of HCC cells, whereas lncRNA Ftx knockdown resulted in the opposite effects. Furthermore, lncRNA Ftx affected the activity and expression of key enzymes in carbohydrate metabolism, suggesting that lncRNA Ftx may be involved in aerobic glycolysis in HCC. The measurement of glucose consumption, lactate production and glucose transporter expression further supported this assumption. Mechanistically, peroxisome proliferator-activated receptor γ (PPARγ) expression in human HCC tissues and cell lines was positively correlated with lncRNA Ftx. Inhibiting PPARγ in Huh7 cells partially abrogated the alterations in glucose uptake, lactate production and relative glycolytic enzyme expression induced by lncRNA Ftx; similarly, PPARγ activation in Bel-7402 cells partially rescued the lncRNA Ftx-mediated alterations. In conclusion, lncRNA Ftx is a promoter of the Warburg effect and tumor progression, partly via the PPARγ pathway, and may serve as a promising therapeutic target for HCC treatment.

Abnormally expressed long noncoding RNAs (lncRNAs) have been reported to affect the occurrence and progression of hepatocellular carcinoma (HCC) by modulating the autophagy axis. However, none of studies has explored the clinical significance of these autophagy-related lncRNAs in HCC comprehensively. In this study, the RNA-seq, miRNA-seq, and clinical data of normal and HCC patients from the TCGA database and autophagy genes from the Human Autophagy Database were extracted. Subsequently, we screened out 78 differentially expressed autophagy-related lncRNAs, and four prognostic-related lncRNAs (LUCAT1, AC099850.3, ZFPM2-AS1, and AC009005.1) were eventually used to develop the prognostic model. This signature could be regarded as an independent prognostic signature for HCC patients and has the highest prediction efficiency than other clinicopathological factors for the 1-, 3-, and 5-year survival ( , respectively). Additionally, regardless of whether the clinical information is complete for HCC patients, the autophagy-related lncRNA model shows a good predictive power for the overall survival. Importantly, the coexpression network of 4 lncRNAs and 11 autophagy-related genes was constructed. Moreover, based on the bioinformatic analyses, our results found that LUCAT1 and ZFPM2-AS1 may affect the autophagic activity in HCC through the hsa-miR-495-3p/DLC1 and hsa-miR-515-5p/DAPK2 axis, respectively. In conclusion, we establish an effective prognostic model for HCC patients and shed new light on the autophagy-related regulatory mechanisms of the identified lncRNAs.

Background: Given poor prognosis and the lack of efficient therapy for advanced hepatocellular carcinoma, immunotherapy has emerged as an increasingly important role. However, there were few reports on the correlation between immune‐related genes and HCC. The purpose of this study is to construct a novel immune‐related gene‐based prognostic signature for HCC and to explore the potential mechanisms.Methods: We organized expression data of 374 HCC samples and 50 nontumor samples from TCGA database. A robust signature was constructed by Cox regression analysis based on the immune‐related genes, which were filtered by differential genes analysis and Cox regression analysis. Then, the correlation analysis between the signature and clinical characteristics was conducted. And the signature was validated in ICGC database. Furthermore, the relationships between immune cell infiltration and the signature were explored by bioinformatics analysis.Results: Seven genes‐based model (Risk score = BIRC5 * 0.0238 + FOS * 0.0055 + DKK1 * 0.0085 + FGF13 * 0.3432 + IL11 * 0.0135 + IL17D * 0.0878 + SPP1 * 0.0003) was constructed eventually and it was proved to be an independent prognostic factor for HCC patients. The signature‐calculated risk scores were shown to be positively correlated with the infiltration of these five immune cells, including macrophages, neutrophils, CD8+T, dendritic, and B cells. And the results suggested that high amplication of BIRC5, FGF13, IL11, IL17D, and SPP1 were more likely correlated with immune cell infiltration. Finally, PPI network, TFs‐based regulatory network and gene enrichment plots were performed to show potential molecular mechanisms.Conclusion: We construct a robust immune‐related gene‐based prognostic signature with seven genes and explore potential mechanisms about it, which may contribute to the immunotherapy research for HCC.

The receptor tyrosine kinases (RTKs) family is well-recognized as vital targets for the treatment of hepatocarcinoma cancer (HCC) clinically, whereas the survival benefit of target therapy sorafenib is not satisfactory for liver cancer patients due to metastasis. EGFR and MET are two molecules of the RTK family that were related to the survival time of liver cancer patients and resistance to targeted therapy in clinical reports. However, the mechanism and clinical therapeutic value of EGFR/MET in HCC metastasis are still not completely clarified. The study confirmed that EGFR/MET was highly expressed in HCC cells and tissues and the phosphorylation was stable after metastasis. The expression of EGFR/MET was up-regulated in circulating tumor microemboli (CTM) to accelerate IL-8 production and resistance to the lethal effect of leukocytes. Meanwhile, highly expressed EGFR/MET effectively regulated the Ras/MAPK pathway and stabilized suspended HCC cells by facilitating proliferation and inhibiting apoptosis. Moreover, EGFR/MET promoted phosphorylation of hetero-RTKs, which was dependent on high-energy phosphoric acid compounds rather than their direct interactions. In conclusion, highly expressed EGFR/MET could be used in CTM identification and suitable for preventing metastasis of HCC in clinical practice.

The activation of liver macrophages is closely related to liver injury after HBV infection. Our previous results demonstrated that HBeAg played a key role in inducing macrophage activation. As we all know, miRNAs are involved in the regulation of multiple immune cell functions. Meanwhile, we have shown that miR‐155 positively regulates HBeAg‐induced macrophage activation and accelerates liver injury. Subsequently, based on our previous miRNA sequencing results, we further evaluated the role of miR‐212‐3p called ‘neurimmiR’ in HBeAg‐induced macrophages in this study. First, miR‐212‐3p expression was significantly elevated in HBeAg‐treated macrophages. Meanwhile, we found up‐regulation of miR‐212‐3p significantly decreased the production of cytokines, whereas knockdown of miR‐212‐3p held the opposite effect by gains and losses of function. Mechanically, although MAPK signal pathway, including ERK, JNK and p38, was activated in HBeAg‐induced macrophages, only ERK promoted the expression of miR‐212‐3p via transcription factor CREB, which was able to bind to the promoter of miR‐212‐3p verified by ChIP assay. Moreover, we further indicated that up‐regulated miR‐212‐3p inhibited HBeAg‐induced inflammatory cytokine production through targeting MAPK1. In conclusion, miR‐212‐3p was augmented in HBeAg‐stimulated macrophages via ERK/CREB signal pathway and the elevated miR‐212‐3p suppressed inflammatory cytokine production induced by HBeAg through targeting MAPK1.