Cancer-associated fibroblasts (CAFs) are one of the most enriched components of Hepatocellular carcinoma (HCC) microenvironment, which are tightly related to the metastasis and invasion of HCC. We identified a mechanism by which CAF-derived chemokine CCL5 enhanced HCC metastasis by triggering the HIF1α/ZEB1 axis. We demonstrated that CAFs derived from HCC tissues promoted the migration and invasion of HCC cells and facilitated metastasis to the lung of NOD/SCID mice. Then the chemokine antibody array elucidated the higher chemokine CCL5 level secreted by CAFs than by paracancerous tissue fibroblasts (PTFs). Mechanistically, we found that CAF-derived CCL5 inhibited the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF1α) by binding to specific receptors, maintained HIF1α under normoxia, thereby up-regulated the downstream gene zinc finger enhancer-binding protein 1 (ZEB1) and induced epithelial-mesenchymal transition (EMT), ultimately validating its ability to promote lung metastasis of HCC. And this novel mechanism may have association with poor prognosis. Taken together, targeting CAF-derived CCL5 mediated HIF1α/ZEB1 cascade possibly propose a new therapeutic route for HCC.

Ten compounds were isolated and identified from green vegetable soya beans, of which five are new triterpenoid saponins (1-5) and five are known compounds (6-10). The chemical structures of the five triterpenoid saponins (1-5) were elucidated to be 3β,24-dihydroxy-22β,30-epoxy-30-oxoolean-12-en 3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-xylopyranosyl-(1 → 2)-β-d-glucuronopyranoside, 1; 3β,24-dihydroxy-22β,30-epoxy-30-oxoolean-12-en 3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-(3″-O-formyl)-galactopyranosyl-(1 → 2)-β-d-glucuronopyranoside, 2; 22-keto-3β,24-dihydroxy oleanane-12-ene 3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-(3″-O-formyl)-galactopyranosyl-(1 → 2)-β-d-glucuronopyranoside, 3; 3β,22β,24-trihydroxy oxyolean-18(19)-ene-29-acid 3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-galactopyranosyl-(1 → 2)-β-d-glucuronopyranoside, 4; and punicanolic acid 3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-galactopyranosyl-(1 → 2)-β-d-glucuronopyranoside, 5 from the spectroscopic data (IR, GTC/FID, HR-ESI-MS, and 1D and 2D NMR). The nitric oxide release inhibitions of compounds 1-10 in LPS-stimulated RAW264.7 cells were evaluated, and the data suggested that compounds 1, 2, and 5 might possess moderate anti-inflammatory activities, with IC values of 18.8, 16.1, and 13.2 μM, respectively.

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