No abstract

Metastasis followed by the tumor development is the primary cause of death for cancer patients. However, the underlying molecular mechanisms of how the growth of tumor resulted in the immune suppression, especially at the blood-enriched organ such as liver, were largely unknown. In this report, we studied the liver immune response of tumor-bearing (TB) mice using concanavalin A (Con A)-induced hepatitis model. We demonstrated that TB mice displayed an immune suppression phenotype, with attenuated alanine aminotransferase levels and liver damage upon Con A treatment. We also elucidated that large amounts of myeloid-derived suppressor cells (MDSCs) being influx into the liver in TB mice and these MDSCs were essential for liver immune suppression through both depletion and reconstitution approaches. We further determined that these MDSCs selectively suppressed the IFN-γ production deriving from NKT cells through membrane-bound transforming growth factor β (TGF-β). Finally, we defined a tumor-derived TGF-β-triggered CXCL1/2/5- and CXCR2-dependent recruitment of MDSC into the liver. In summary, our results defined a novel mechanism of liver immune suppression triggered by growing living tumor and provided possible therapeutic targets against these MDSCs.

Esophageal cancer is one of the most prevalent forms of cancer and has a particularly high mortality rate due to early metastasis; however, the underlying mechanisms of its formation and progression remain unclear. The present study performed immunohistochemical analysis and observed that the expression of activating transcription factor 3 (ATF3) was reduced in esophageal squamous cell carcinoma (ESCC) in comparison with non-tumor adjacent tissues. By contrast, inhibitor of DNA binding 1 (ID1) was overexpressed in ESCC tissues, demonstrating an inverse correlation with ATF3 (P<0.01). In ESCC EC109 and KYSE450 cells lines, transfection with an ATF3-overexpression plasmid resulted in the inhibition of cell proliferation, motility and migration, which was associated with the induction of E-cadherin expression and inhibition of cyclin D1 and Twist. Notably, ATF3 exerted an inverse regulatory interaction with ID1. The results of the present study provide additional evidence of the tumor suppressive features of ATF3 and demonstrate a novel mechanism of ATF3-mediated inhibition of cancer metastasis in esophageal cancer.

Abstract. Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl from lysine residues in histones and other proteins, which results in gene transcriptional repression and subsequent changes in signaling events. HDACs inhibitors (HDACIs) have been used to reverse the aberrant epigenetic changes associated with cancer. However, the effects of HDACIs on epithelial-mesenchymal transition (EMT) in human cancer cells remain unclear. EMT is a fundamental process governing morphogenesis in multicellular organisms and promotes cancer invasion and metastasis. In this study, human cancer cells were treated with the HDACI trichostatin A (TSA). TSA was found to induce mesenchymal-like morphological changes in BGC-823 human gastric cancer and MCF-7 breast cancer cells, and increase the expression levels of the mesenchymal markers Vimentin and Twist. However, the expression levels of the epithelial cell marker E-cadherin were also increased in response to TSA treatment, while cell migration was reduced by TSA. Furthermore, TSA decreased cancer cell colony formation in BGC-823 and MCF-7 cells, and led to the deregulation of β-catenin, a critical signaling molecule involved in EMT. In conclusion, the results suggested that TSA exhibits dual functions in EMT induction and inhibition in human cancer cells, but the detailed mechanisms require further investigation.

Dendritic cells (DCs) play critical roles in initiating and regulating innate immunity as well as adaptive immune responses. However, the role of conventional dendritic cells (cDCs) in concanavalin A (ConA)-induced fulminant hepatitis is unknown. In this study, we demonstrated that depletion of cDCs using either CD11c-diphtheria toxin receptor transgenic mice (DTR Tg) mice or anti-CD11c antibody reduced the severity of liver injury significantly, indicating a detrimental role of cDCs in ConA-induced hepatitis. We elucidated further the pathological role of cDCs as being the critical source of interleukin (IL)-12, which induced the secretion of interferon (IFN)-γ by natural killer (NK) T cells. Reconstitution of cDCs-depleted mice with IL-12 restored ConA-induced hepatitis significantly. Furthermore, we determined that NK T cells were the target of DC-derived IL-12, and NK T cells contributed to liver inflammation and injury through production of IFN-γ. In summary, our study demonstrated a novel function of cDCs in mediating ConA-induced hepatitis through regulating IFN-γ secretion of NK T cells in an IL-12-dependent fashion. Targeting cDCs might provide potentially therapeutic applications in treating autoimmune related liver diseases.