Loss of miR-192-5p initiates a hyperglycolysis and stemness positive feedback in hepatocellular carcinoma

Abstract

Background Emerging studies revealed that cancer stem cells (CSCs) possessed peculiar metabolic properties, which however remained largely unknown in hepatocellular carcinoma (HCC). Genetic silencing of liver-abundant miR-192-5p was a key feature for multiple groups of CSC-positive HCCs. We thus aimed to investigate essential metabolic features of hepatic CSCs via using HCCs with miR-192-5p silencing as a model. Methods Datasets from two independent HCC cohorts were used. Data integration analyses of miR-192-5p with metabolome and mRNA transcriptome data in HCC Cohort 1 were performed to investigate miR-192-5p related metabolic features, which was further validated in Cohort 2. Cellular and molecular assays were performed to examine whether and how miR-192-5p regulated the identified metabolic features. Co-culture systems consisting of HCC cells and LX2 (human hepatic stellate cell line) or THP1 (human monocyte cell line) were established to explore effects of the identified metabolic properties on stemness features of HCC cells via interacting with co-cultured non-tumor cells. Results High levels of glycolysis-related metabolites and genes were present in HCCs with low miR-192-5p and CSC-positive HCCs in two independent HCC cohorts. miR-192-5p knockout cells displayed CSC features and miR-192-5p loss led to an enhanced glycolytic phenotype via upregulating three bona fide targets, GLUT1 and PFKFB3 (two glycolytic enzymes) and c-Myc (regulating glycolytic genes’ expression). Meanwhile, c-Myc suppressed miR-192-5p transcription, ensuring a low-miR-192-5p/high-c-Myc loop to maintain hyperglycolysis. Moreover, over-produced lactic acid from hyperglycolytic HCC cells stimulated the ERK phosphorylation of co-cultured LX2 and THP1 non-tumor cells partially via NDRG3 and MCT1, which in turn promoted cell malignancy and stemness of HCC cells. Consistently, HCC patients with low level of miR-192-5p in their tumor tissues and high level of NDRG3 or MCT1 in their non-tumor tissues had the shortest overall survival. Conclusions In CSC-positive HCCs, miR-192-5p loss enhanced glycolysis and over produced lactate might further increase HCC malignant features via interacting with environmental non-tumor cells.

Long Non-Coding RNA LINC01572 Promotes Hepatocellular Carcinoma Progression via Sponging miR-195-5p to Enhance PFKFB4-Mediated Glycolysis and PI3K/AKT Activation

“…PFKFB4 is a key glycolysis regulator which activates the rate-limiting enzyme phosphofructokinase-1 (PFK-1) in glycolysis via its product fructose-2,6-biphosphate and has been proposed recently as a potential oncogene in HCC ( Shen et al, 2021 ). Considering the significance of glycolysis in HCC malignancy ( Hu L. et al, 2019 ; Feng et al, 2020 ; Gu et al, 2020 ), we reckoned that LINC01572 might have a glycolysis-promoting potential via increase in the PFKFB4 level. In line with this notion, we found that LINC01572 knockdown significantly inhibited the glycolytic process, which was effectively reversed by PFKFB4 overexpression ( Figures 7A,C,E ), whereas LINC01572 overexpression promoted HCC glycolysis, and PFKFB4 silencing remarkably blunted this effect ( Figures 7B,D,F,H ).…”

miR-3682-3p directly targets FOXO3 and stimulates tumor stemness in hepatocellular carcinoma via a positive feedback loop involving FOXO3/PI3K/AKT/c-Myc

“…Multiple hepatic CSC biomarkers have already been identified. In this study, we have added a genetic signature of these liver CSCs and revealed the signaling pathways that regulate HCC[ 27 ].…”

Genistein Restricts the Epithelial Mesenchymal Transformation (EMT) and Stemness of Hepatocellular Carcinoma via Upregulating miR-1275 to Inhibit the EIF5A2/PI3K/Akt Pathway

“…In addition, it has also been widely reported that miRNAs play an important role in dominating the EMT and stemness of HCC [ 2 , 26 ]. For example, miR-192-5p and miR-568 were found to regulate the stemness behavior to affect HCC progression [ 27 , 28 ]. In our study, we found for the first time that miR-1275 can be positively regulated by genistein in HCC cells through transcriptome sequencing and series experiments.…”