Abstract
BackgroundEmerging 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.MethodsDatasets 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.ResultsHigh 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.ConclusionsIn 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.
Highlights
Emerging studies revealed that cancer stem cells (CSCs) possessed peculiar metabolic properties, which remained largely unknown in hepatocellular carcinoma (HCC)
Similar data were seen in HLE cells as well as in HLE cells cocultured with LX2 and HL7702 (Supplementary Fig. S4e-f). These results demonstrate that HCC cells with loss of miR-192-5p actively utilize glucose from their environment to ensure a hyperglycolysis status
PFKFB3, GLUT1, and MYC presented higher levels in HCC192Low tumors compared to HCC192High tumors (Supplementary Fig. S5b-c). These results indicate that PFKFB3, GLUT1, and c-Myc are miR-192-5p targets and are involved in the hyperglycolysis caused by miR-192-5p loss
Summary
Emerging studies revealed that cancer stem cells (CSCs) possessed peculiar metabolic properties, which remained largely unknown in hepatocellular carcinoma (HCC). Studies of cancer metabolism have revealed the important roles of metabolic reprogramming in cancer cells for proliferation, metastasis and drug resistance [1, 2]. A small population of cancer cells exhibit a high capacity of self-renewal and tumor initiation in NOD/SCID mice, which are referred to as cancer stem cells (CSCs). CSCs are considered to be responsible for tumor initiation, therapy resistance as well as recurrence, and rising attentions have been placed on CSC metabolism [3,4,5]. Exploiting metabolic vulnerability of CSCs may provide new effective cancer therapies to diminish tumor recurrence and metastasis
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