ABSTRACT
Axon guidance protein Semaphorin 3E (Sema3E) promotes tumor metastasis and suppresses tumor cell death. Here, we demonstrated that Sema3E was decreased in gastric cancer. Its levels were inversely associated with tumor progression. Levels of Sema3E were associated with low p300 and high class I histone deacetylase (class I HDAC). Ectopic expression of Sema3E inhibited proliferation and colony formation of gastric cancer cell lines in vitro and xenografts in vivo. Sema3E overexpression inhibited migration and invasion of gastric cancer cells, which was associated with induction of E-cadherin and reduction of Akt and ERK1/2 phosphorylation. We suggest that silencing of Sema3E contributes to the pathogenesis of gastric cancer.
Subject(s)
Semaphorins/genetics , Stomach Neoplasms/genetics , Animals , Cell Line, Tumor , Down-Regulation , Epigenomics , Female , HEK293 Cells , Heterografts , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Semaphorins/biosynthesis , Semaphorins/metabolism , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathologyABSTRACT
The epigenetic dysregulation of tumor suppressor genes plays an important role in many cancers, including hepatocellular carcinoma (HCC). In this study, we identified a new gene, family with sequence similarity 43, member B (FAM43B), based on a previous genome-wide approach. FAM43B was significantly downregulated in 60% (24/40) HCC specimens as compared to non-HCC livers. Enforced FAM43B overexpression could suppress cell growth and colony formation in vitro, and induce cell cycle delay, whereas FAM43B knockdown enhanced cell growth. The expression level of FAM43B was found related to the methylation level of FAM43B promoter in HCC cell lines and HCC specimens. The collective data suggest that the expression of FAM43B was regulated by methylation and the epigenetic silencing of FAM43B could contribute to HCC tumorigenesis by regulating cell proliferation.
Subject(s)
Carcinoma, Hepatocellular/genetics , Cell Proliferation , DNA Methylation , Epigenesis, Genetic , Genes, Tumor Suppressor , Liver Neoplasms/genetics , Carcinoma, Hepatocellular/metabolism , Cell Cycle/genetics , Cell Line, Tumor , Cell Nucleus/metabolism , Down-Regulation , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/metabolism , Organ Specificity , Phylogeny , Promoter Regions, Genetic , RNA InterferenceABSTRACT
LPS is an immunostimulatory component of Gram-negative bacteria. Acting on the immune system in a systemic fashion, LPS exposes the body to the hazard of septic shock. In this study we report that cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2/Crispld2; human and mouse/rat versions, respectively), expressed by multitissues and leukocytes, is a novel LPS-binding protein. As a serum protein, median CRISPLD2 concentrations in health volunteers and umbilical cord blood samples are 607 microg/ml and 290 microg/ml, respectively. Human peripheral blood granulocytes and mononuclear cells including monocytes, NK cells, and T cells spontaneously release CRISPLD2 (range, 0.2-0.9 microg/ml) and enhance CRISPLD2 secretion (range, 1.5-4.2 microg/ml) in response to stimulation of both LPS and humanized anti-human TLR4-IgA Ab in vitro. CRISPLD2 exhibits significant LPS binding affinity similar to that of soluble CD14, prevents LPS binding to target cells, reduces LPS-induced TNF-alpha and IL-6 production, and protects mice against endotoxin shock. In in vivo experiments, serum Crispld2 concentrations increased in response to a nontoxic dose of LPS and correlated negatively with LPS lethality, suggesting that CRISPLD2 serum concentrations not only are indicators of the degree of a body's exposure to LPS but also reflect an individual's LPS sensitivity.
