Fig. 4.

Inflammatory mediators in the microenvironment of hepatocellular carcinoma. HIF-1α promotes vasculogenic mimicry (VM) and epithelial-to-mesenchymal transition (EMT) by upregulation of LOXL2. HIF-1β downregulates E-cadherin expression via the Notch signaling pathway, and interacts with numerous oncogene-encoded proteins including epidermal growth factor receptor (EGFR), c-Myc, K-Ras, even some lncRNAs, such as NEAT1, to promote EMT. CXCL1 participates in tumor promotion by stimulating mitochondrial metabolism and activating EMT. CXCL10 upregulates MMP-2 expression to participate in EMT; MMP-16 and MMP-9 are also key factors. cPLA2 plays an opposing role in TGF-β-induced signaling pathways by inhibiting Smad2/3 phosphorylation and promoting activation of PI3K/AKT/ERK signaling pathways to mediate EMT. PD-1/PD-L1 induces EMT via the PI3K/AKT and ERK/MEK signaling pathways, and upregulation of SREBP-1c