No abstract

Although anti‐angiogenic therapies (AATs) have some effects against multiple malignancies, they are limited by subsequent tumor vasculogenesis and progression. To investigate the mechanisms by which tumor vasculogenesis and progression following AATs, we transfected microRNA (miR)‐9 into human umbilical vein endothelial cells (HUVECs) to mimic the tumor‐associated endothelial cells in hepatocellular carcinoma and simulated the AATs in vitro and in vivo. We found that administration of the angiogenesis inhibitor vandetanib completely abolished miR‐9‐induced angiogenesis and promoted autophagy in HUVECs, but induced the release of vascular endothelial growth factor (VEGF)‐enriched exosomes. These VEGF‐enriched exosomes significantly promoted the formation of endothelial vessels and vasculogenic mimicry in hepatocellular carcinoma and its progression in mice. Anti‐autophagic therapy is proposed to improve the efficacy of AATs. However, similar effects by AATs were observed with the application of anti‐autophagy by 3‐methyladenine. Our results revealed that tumor vasculogenesis and progression after AATs and anti‐autophagic therapies were due to the cross‐talk between endothelial cells and tumor cells via VEGF‐enriched exosomes. These findings provide a critical insight into a new interpretation of why AATs have not achieved expected outcomes. They also suggest that control of exosome release or alteration of exosome cargo composition to inhibit tumor vasculogenesis may augment the anti‐angiogenic and anti‐autophagic therapies for tumors. Support or Funding Information Supported by National Natural Science Foundation of China (Grant no.11402153). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sphingosine-1-phosphate (S1P) induces epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). However, its underlying mechanism remains largely unknown. In the present study, we investigated the correlation between S1P and syndecan-1 in HCC, the molecular mechanism involved, as well as their roles in EMT of HCC. Results revealed a high serum S1P level presents in patients with HCC, which positively correlated with the serum syndecan-1 level. A significant inverse correlation existed between S1P1 and syndecan-1 in HCC tissues. S1P elicits activation of the PI3K/AKT signaling pathways via S1P1, which triggers HPSE, leading to increases in expression and activity of MMP-7 and leading to shedding and suppression of syndecan-1. The loss of syndecan-1 causes an increase in TGF-β1 production. The limited chronic increase in TGF-β1 can convert HCC cells into a mesenchymal phenotype via establishing an MMP-7/Syndecan-1/TGF-β autocrine loop. Finally, TGF-β1 and syndecan-1 are essential for S1P-induced epithelial to mesenchymal transition. Taken together, our study demonstrates that S1P induces advanced tumor phenotypes of HCC via establishing an MMP-7/syndecan-1/TGF-β1 autocrine loop, and implicates targetable S1P1-PI3K/AKT-HPSE-MMP-7 signaling axe in HCC metastasis.

In this report, we rationally designed and fabricated P-C3N4/ZnIn2S4 nanocomposites by in situ immobilizing ZnIn2S4 nanosheets onto the surface of mesoporous P-doped graphite carbon nitrogen (P-C3N4) nanosheets in a mixed solvothermal environment; their application to the photoreduction of 4-nitroaniline was used to estimate the photocatalytic performance. Different to the template route, here the mesoporous P-C3N4 nanosheets were prepared with a template-free strategy. The as-fabricated P-C3N4/ZnIn2S4 nanocomposites were systematically characterized by analyzing the phase structure, chemical components, electronic and optical properties and separation of charge carrier pairs. More importantly, these P-C3N4/ZnIn2S4 heterostructures have been proven to be highly efficient visible light responsive photocatalysts for photo-reduction, and meanwhile exhibit excellent photo-stability during recycling runs. The sufficient evidence reveals that the significantly improved photocatalytic performance is mainly attributed to the more efficient charge carrier separation based on the construction of a close heterogeneous interface. This work may provide new insights into the utilization of P-C3N4/ZnIn2S4 nanocomposites as visible light driven photocatalysts for comprehensive organic transformations in the field of fine chemical engineering.

Interleukin-8 (IL-8) is a common inflammatory factor, which involves in various non-specific pathological processes of inflammation. It has been found that increased endothelial permeability accompanied with high expression of IL-8 at site of injured endothelium and atherosclerotic plaque at early stages, suggesting that IL-8 participated in regulating endothelial permeability in the developing processes of vascular disease. The purpose of this study is to investigate the regulation effects of IL-8 on the vascular endothelial permeability, and the mRNA and protein expression of tight junction components (i.e., ZO-1, Claudin-5 and Occludin). Endothelial cells were stimulated by IL-8 with the dose of 50, 100 and 200 ng/mL, and duration of 2, 4, 6, 8h, respectively. The mRNA and protein expression level of tight junction components with IL-8 under different concentration and duration was examined by RT-PCR and Western blot, respectively. Meanwhile, the integrins induced focal adhesions event with IL-8 stimulation was also investigated. The results showed that IL-8 regulated the permeability of endothelium by down-regulation of tight junction in a dose- and time-dependence manner, but was not by integrins induced focal adhesions. This finding reveals the molecular mechanism in the increase of endothelial cell permeability induced by IL-8, which is expected to provide a new idea as a therapeutic target in vascular diseases.