The communication between tumor-derived elements and stroma in the metastatic niche has a critical role in facilitating cancer metastasis. Yet, the mechanisms tumor cells use to control metastatic niche formation are not fully understood. Here we report that in the lung metastatic niche, high-metastatic hepatocellular carcinoma (HCC) cells exhibit a greater capacity to convert normal fibroblasts to cancer-associated fibroblasts (CAFs) than low-metastatic HCC cells. We show high-metastatic HCC cells secrete exosomal miR-1247-3p that directly targets B4GALT3, leading to activation of β1-integrin–NF-κB signaling in fibroblasts. Activated CAFs further promote cancer progression by secreting pro-inflammatory cytokines, including IL-6 and IL-8. Clinical data show high serum exosomal miR-1247-3p levels correlate with lung metastasis in HCC patients. These results demonstrate intercellular crosstalk between tumor cells and fibroblasts is mediated by tumor-derived exosomes that control lung metastasis of HCC, providing potential targets for prevention and treatment of cancer metastasis.

Hepatocellular carcinoma (HCC) cells often invade the portal venous system and subsequently develop into portal vein tumour thrombosis (PVTT). Long noncoding RNAs (lncRNAs) have been associated with HCC, but a comprehensive analysis of their specific association with HCC metastasis has not been conducted. Here, by analysing 60 clinical samples' RNA-seq data from 20 HCC patients, we have identified and characterized 8,603 candidate lncRNAs. The expression patterns of 917 recurrently deregulated lncRNAs are correlated with clinical data in a TCGA cohort and published liver cancer data. Matched array data from the 60 samples show that copy number variations (CNVs) and alterations in DNA methylation contribute to the observed recurrent deregulation of 235 lncRNAs. Many recurrently deregulated lncRNAs are enriched in co-expressed clusters of genes related to cell adhesion, immune response and metabolic processes. Candidate lncRNAs related to metastasis, such as HAND2-AS1, were further validated using RNAi-based loss-of-function assays. Thus, we provide a valuable resource of functional lncRNAs and biomarkers associated with HCC tumorigenesis and metastasis.

Vitamin C (L-ascorbic acid, ascorbate, VC) is a potential chemotherapeutic agent for cancer patients. However, the anti-tumor effects of pharmacologic VC on hepatocellular carcinoma (HCC) and liver cancer stem cells (CSCs) remain to be fully elucidated. Panels of human HCC cell lines as well as HCC patient-derived xenograft (PDX) models were employed to investigate the anti-tumor effects of pharmacologic VC. The use of VC and the risk of HCC recurrence were examined retrospectively in 613 HCC patients who received curative liver resection as their initial treatment. In vitro and in vivo experiments further demonstrated that clinically achievable concentrations of VC induced cell death in liver cancer cells and the response to VC was correlated with sodium-dependent vitamin C transporter 2 (SVCT-2) expressions. Mechanistically, VC uptake via SVCT-2 increased intracellular ROS, and subsequently caused DNA damage and ATP depletion, leading to cell cycle arrest and apoptosis. Most importantly, SVCT-2 was highly expressed in liver CSCs, which promoted their self-renewal and rendered them more sensitive to VC. In HCC cell lines xenograft models, as well as in PDX models, VC dramatically impaired tumor growth and eradicated liver CSCs. Finally, retrospective cohort study showed that intravenous VC use was linked to improved disease-free survival (DFS) in HCC patients (adjusted HR = 0.622, 95% CI 0.487 to 0.795, p < 0.001). Our data highlight that pharmacologic VC can effectively kill liver cancer cells and preferentially eradicate liver CSCs, which provide further evidence supporting VC as a novel therapeutic strategy for HCC treatment.

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Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5′-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62’s aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.