USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4.

Herein, we aimed to elucidate the molecular and cellular mechanism in which ubiquitin-specific protease 8 (USP8) is implicated in liver cancer progression via TRAF6-mediated signal. USP8 induces the deubiquitination of TRAF6, TAB2, TAK1, p62, and BECN1, which are pivotal roles for NF-κB activation and autophagy induction. Notably, the LIHC patient with low USP8 mRNA expression showed markedly shorter survival time, whereas there was no significant difference in the other 18-human cancers. Importantly, the TCGA data analysis on LIHC and transcriptome analysis on the USP8 knockout (USP8KO) SK-HEP-1 cells revealed a significant correlation between USP8 and TRAF6, TAB2, TAK1, p62, and BECN1, and enhanced NF-κB-dependent and autophagy-related cancer progression/metastasis-related genes in response to LPS stimulation. Furthermore, USP8KO SK-HEP-1 cells showed an increase in cancer migration and invasion by TLR4 stimulation, and a marked increase of tumorigenicity and metastasis in xenografted NSG mice. The results demonstrate that USP8 is negatively implicated in the LIHC progression through the regulation of TRAF6-mediated signal for the activation of NF-κB activation and autophagy induction. Our findings provide useful insight into the LIHC pathogenesis of cancer progression.

Human delta like 1-expressing human mesenchymal stromal cells promote human T cell development and antigen-specific response in humanized NOD/SCID/IL-2R[Formula: see text]null (NSG) mice.

Human delta-like 1 (hDlk1) is known to be able to regulate cell fate decisions during hematopoiesis. Mesenchymal stromal cells (MSCs) are known to exhibit potent immunomodulatory roles in a variety of diseases. Herein, we investigated in vivo functions of hDlk1-hMSCs and hDlk1+hMSCs in T cell development and T cell response to viral infection in humanized NOD/SCID/IL-2Rγnull (NSG) mice. Co-injection of hDlk1-hMSC with hCD34+ cord blood (CB) cells into the liver of NSG mice markedly suppressed the development of human T cells. In contrast, co-injection of hDlk1+hMSC with hCD34+ CB cells into the liver of NSG dramatically promoted the development of human T cells. Human T cells developed in humanized NSG mice represent markedly diverse, functionally active, TCR V[Formula: see text] usages, and the restriction to human MHC molecules. Upon challenge with Epstein-Barr virus (EBV), EBV-specific hCD8+ T cells in humanized NSG mice were effectively mounted with phenotypically activated T cells presented as hCD45+hCD3+hCD8+hCD45RO+hHLA-DR+ T cells, suggesting that antigen-specific T cell response was induced in the humanized NSG mice. Taken together, our data suggest that the hDlk1-expressing MSCs can effectively promote the development of human T cells and immune response to exogenous antigen in humanized NSG mice. Thus, the humanized NSG model might have potential advantages for the development of therapeutics targeting infectious diseases in the future.