Promotion of Lung Cancer Metastasis by SIRT2-Mediated Extracellular Protein Deacetylation.

Acetylation of extracellular proteins has been observed in many independent studies where particular attention has been given to the dynamic change of the microenvironmental protein post-translational modifications. While extracellular proteins can be acetylated within the cells prior to their micro-environmental distribution, their deacetylation in a tumor microenvironment remains elusive. Here it is described that multiple acetyl-vWA domain-carrying proteins including integrin ß3 (ITGB3) and collagen 6A (COL6A) are deacetylated by Sirtuin family member SIRT2 in extracellular space. SIRT2 is secreted by macrophages following toll-like receptor (TLR) family member TLR4 or TLR2 activation. TLR-activated SIRT2 undergoes autophagosome translocation. TNF receptor associated factor 6 (TRAF6)-mediated autophagy flux in response to TLR2/4 activation can then pump SIRT2 into the microenvironment to function as extracellular SIRT2 (eSIRT2). In the extracellular space, eSIRT2 deacetylates ITGB3 on aK416 involved in cell attachment and migration, leading to a promotion of cancer cell metastasis. In lung cancer patients, significantly increased serum eSIRT2 level correlates with dramatically decreased ITGB3-K416 acetylation in cancer cells. Thus, the extracellular space is a subcellular organelle-like arena where eSIRT2 promotes cancer cell metastasis via catalyzing extracellular protein deacetylation.

Derivation and applications of human hepatocyte-like cells.

Human hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) promise a valuable source of cells with human genetic background, physiologically relevant liver functions, and unlimited supply. With over 10 years' efforts in this field, great achievements have been made. HLCs have been successfully derived and applied in disease modeling, toxicity testing and drug discovery. Large cohorts of induced pluripotent stem cells-derived HLCs have been recently applied in studying population genetics and functional outputs of common genetic variants in vitro. This has offered a new paradigm for genome-wide association studies and possibly in vitro pharmacogenomics in the nearly future. However, HLCs have not yet been successfully applied in bioartificial liver devices and have only displayed limited success in cell transplantation. HLCs still have an immature hepatocyte phenotype and exist as a population with great heterogeneity, and HLCs derived from different hPSC lines display variable differentiation efficiency. Therefore, continuous improvement to the quality of HLCs, deeper investigation of relevant biological processes, and proper adaptation of recent advances in cell culture platforms, genome editing technology, and bioengineering systems are required before HLCs can fulfill the needs in basic and translational research. In this review, we summarize the discoveries, achievements, and challenges in the derivation and applications of HLCs.

Porphyromonas gingivalis-derived lipopolysaccharide causes excessive hepatic lipid accumulation via activating NF-κB and JNK signaling pathways.

BACKGROUND: Porphyromonas gingivalis is the main pathogen of periodontal disease affecting over half of the worldwide adult population. Recent studies have shown that P. gingivalis is related to the development of non-alcoholic fatty liver disease (NAFLD), a global major chronic liver disease, especially in developed countries. However, how P. gingivalis contributes to the pathogenesis of NAFLD has not been fully clarified. We aimed to conduct a preliminary exploration of the underlying mechanism of P. gingivalis infection in the development of NAFLD. METHODS: Human hepatocellular cells HepG2 were incubated with/without oleic acid (OA) and tested for lipid accumulation upon stimulation by lipopolysaccharide (LPS) derived from P. gingivalis or Escherichia coli. Intracellular lipid droplet formation was analyzed and quantified by Oil Red O staining. The involvement of signaling pathway molecules and pro-inflammatory cytokines related to NF-κB and MAPKs were examined with Western blot and quantitative real-time PCR (qRT-PCR) analyses and further evaluated with inhibitor treatment and RNA interference. RESULTS: HepG2 cells accumulated more intracellular lipids when stimulated with P. gingivalis LPS, as compared to cells treated with E. coli LPS or control. Further pathway analysis demonstrated that after stimulation with P. gingivalis LPS, cells displayed significantly upregulated MyD88 expression, increased phosphorylation of p65 and JNK, and more release of pro-inflammatory cytokines, such as IL-1, IL-8, and TNF-α. In addition, suppression of phosphorylation of p65 and JNK by inhibitors and RNA interference resulted in a reduction in lipid accumulation upon P. gingivalis LPS treatment. CONCLUSIONS: These results suggest that P. gingivalis-derived LPS may contribute to intracellular lipid accumulation and inflammatory reaction of HepG2 cells via the activation of NF-κB and JNK signaling pathways. This study offers a possible explanation to the functional involvement of P. gingivalis infection in the pathological progression of NAFLD. These findings may help design new treatment strategies in NAFLD.

RelB/NF-κB links cell cycle transition and apoptosis to endometrioid adenocarcinoma tumorigenesis.

Dysfunction of nuclear factor-κB (NF-κB) signaling has been causally associated with numerous human malignancies. Although the NF-κB family of genes has been implicated in endometrial carcinogenesis, information regarding the involvement of central regulators of NF-κB signaling in human endometrial cancer (EC) is limited. Here, we investigated the specific roles of canonical and noncanonical NF-κB signaling in endometrial tumorigenesis. We found that NF-κB RelB protein, but not RelA, displayed high expression in EC samples and cell lines, with predominant elevation in endometrioid adenocarcinoma (EEC). Moreover, tumor cell-intrinsic RelB was responsible for the abundant levels of c-Myc, cyclin D1, Bcl-2 and Bcl-xL, which are key regulators of cell cycle transition, apoptosis and proliferation in EEC. In contrast, p27 expression was enhanced by RelB depletion. Thus, increased RelB in human EC is associated with enhanced EEC cell growth, leading to endometrial cell tumorigenicity. Our results reveal that regulatory RelB in noncanonical NF-κB signaling may serve as a therapeutic target to block EC initiation.

Nuclear hormone receptor regulation of microRNAs controls innate immune responses in C. elegans.

Nuclear hormone receptors respond to small molecules such as retinoids or steroids and regulate development. Signaling in the conserved p38/PMK-1 MAP kinase pathway regulates innate immunity. In this study, we show that the Caenorhabditis elegans nuclear receptor DAF-12 negatively regulates the defense against pathogens via the downstream let-7 family of microRNAs, which directly target SKN-1, a gene downstream of PMK-1. These findings identify nuclear hormone receptors as components of innate immunity that crosstalk with the p38/PMK-1 MAP kinase pathway.