The fibroblast growth factor receptor 2-IIIb (FGFR2b) and the vascular endothelial growth factor receptor 2 (VEGFR2) are tyrosine kinases that can promote cell migration and proliferation and have important roles in embryonic development and cancer. Here we show that FGF7/FGFR2b-dependent activation of epidermal growth factor receptor (EGFR)/ERK1/2 signalling and cell migration in epithelial cells require stimulation of the membrane-anchored metalloproteinase ADAM17 and release of heparin-binding epidermal growth factor (HB-EGF). Moreover, VEGF-A/VEGFR2-induced migration of human umbilical vein endothelial cells also depends on EGFR/ERK1/2 signalling and shedding of the ADAM17 substrate HB-EGF. The pathway used by the FGF7/FGFR2b signalling axis to stimulate shedding of substrates of ADAM17, including ligands of the EGFR, involves Src, p38 mitogen-activated protein-kinase and PI3K, but does not require the cytoplasmic domain of ADAM17. Based on these findings, ADAM17 emerges as a central component in a triple membrane-spanning pathway between FGFR2b or VEGFR2 and EGFR/ERK1/2 that is required for cell migration in keratinocytes and presumably also in endothelial cells.

Decidual natural killer (dNK) cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) are expressed on over 60% of dNK cells. Tim-3 1 dNK cells display higher interleukin (IL)-4 and lower tumor necrosis factor (TNF)-a and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 (Gal-9) and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper (Th)2-type cytokines were decreased and Th1-type cytokines were increased in Tim-3 1 but not Tim-3 2 dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.

CXCL12 secreted by human trophoblasts enhances the coordination between trophoblasts and DSCs, via the regulation of MMP9 and MMP2, which may improve the functional materno-fetal interface.

Summary Overabundance of Slug protein is common in human cancer and represents an important determinant underlying the aggressiveness of basal-like breast cancer (BLBC). Despite its importance, this transcription factor is rarely mutated in BLBC, and the mechanism of its deregulation in cancer remains unknown. Here we report that Slug undergoes acetylation-dependent protein degradation and identify the deacetylase SIRT2 as a key mediator of this post-translational mechanism. SIRT2 inhibition rapidly destabilizes Slug, whereas SIRT2 overexpression extends Slug stability. We show that SIRT2 deacetylates Slug protein at lysine residue K116 to prevent Slug degradation. Interestingly, SIRT2 is frequently amplified and highly expressed in BLBC. Genetic depletion and pharmacological inactivation of SIRT2 in BLBC cells reverse Slug stabilization, cause the loss of clinically relevant pathological features of BLBC, and inhibit tumor growth. Our results suggest that targeting SIRT2 may be a rational strategy for diminishing Slug abundance and its associated malignant traits in BLBC.

In spite of the clinical importance of prostate cancer (PCa) bone metastasis, the precise mechanisms for the directed migration of malignant cells remain unclear. In the present study, the expression of CXCR6 in human PCa and benign prostatic hyperplasia samples, and the expression of CXCL16 in human osseous tissues were determined by immunohistochemistry. It was found that the level of CXCR6 protein expression was elevated in human malignant prostate tumors, and CXCL16 was expressed positively by human osteocytes in vivo. The in vitro experiments further confirmed that the PCa cell lines PC3 and LNCap expressed CXCR6 at both the mRNA and protein levels, and exogenous CXCL16 has the potential to stimulate the invasion of PC3 and LNCap. To further elucidate the role of the CXCL16-CXCR6 axis in PCa progression, we compared the expression of CXCR6 and CXCR4 in human PCa tissues and the effects of CXCL16 and CXCL12 on the in vitro invasion of PC3 and LNCap cells. P rostate cancer is a common neoplasm and the second leading cause of cancer death in American men, and its morbidity has also increased in recent years in China.(1,2) Despite advances in early diagnosis and therapeutics of PCa, metastasis to bone is one of the most severe complications and major causes of mortality of PCa.(3,4) Many factors have been implicated in the process of metastasis, but the precise mechanisms for the directed migration and invasion of malignant cells into selective organs at both the cellular and molecular levels remain unclear.Recent studies indicate that tumor cell migration and metastasis are not random processes; rather, chemokines and chemokine receptors may play important roles in determining the metastatic destination of tumor cells.(5,6) For PCa, most investigations focused on the CXCL12-CXCR4 signaling pathway; (7)(8)(9) however, little is known about the relationship between PCa specific metastasis and other chemokines or chemokine receptors.CXCR6, initially described under the names Bonzo, STRL33 and TYMSTR, is a newly characterized chemokine receptor that until now was described to be expressed selectively by subsets of memory/effector T cells, (10) NK cells, (11) NK T cells,and plasma cells.(13) CXCL16, the sole ligand of CXCR6, is a unique CXC chemokine that exists both in a transmembrane form and a soluble form. (14,15) The interaction between CXCL16 and CXCR6 has been shown to mediate multiple biological activities, including selective trafficking of lymphocyte subsets, cell adhesion, cell survival, chronic inflammation, and antitumor immunity. (16)(17)(18)(19)(20) In particular, human bone marrow plasma cells express CXCR6 selectively, and tissues known to be enriched with plasma cells as well as cultured human bone marrow stromal cells express CXCL16 constitutively, (13) implying the importance of the CXCL16-CXCR6 axis in efficient recruitment to target tissues. Furthermore, it has been found that first-trimester human cytotrophoblasts coexpress CXCL16 and CXCR6 as well as secreted CXCL16, which induces their inva...

Human first-trimester DSCs express membrane CXCR4 and TC-derived CXCL12 promotes CXCR4 expression and invasion of DSCs via ligation with CXCR4. Our data highlight the role of CXCL12/CXCR4 axis on the co-operation between TCs and DSCs during human first-trimester pregnancy.

ADAM17 (a disintegrin and metalloproteinase 17) is a cell-surface metalloproteinase that regulates signaling via the epidermal growth factor receptor (EGFR) and has important roles in diseases such as cancer and rheumatoid arthritis. ADAM17 can be activated by stimulation of several tyrosine kinase receptors, raising questions about whether oncogenic tyrosine kinases could also enhance EGFR signaling and activation of ERK via stimulation of ADAM17. The main goal of this study was to evaluate the role of Src in activating ADAM17. We provide evidence that a constitutively active transforming form of Src, the E378G mutant, as well as v-Src enhance ADAM17-mediated shedding of the EGFR-ligand TGFα. Moreover, we demonstrate that constitutive shedding of TGFα can be reduced by inhibition of Src in several cell lines, including COS7, MCF7, PAE and HaCaT cells. Src(E378G)-stimulated shedding of TGFα is abolished in Adam17−/− cells, but can be rescued by wild type ADAM17 and a mutant ADAM17 lacking its cytoplasmic domain. These findings demonstrate that ADAM17 is the principal TGFα sheddase that is activated by Src in a manner that does not require the cytoplasmic domain of ADAM17. Finally, we show that stimulation of ADAM17 by Src(E378G) leads to enhanced paracrine signaling via release of EGFR-ligands into the culture supernatant. These results raise the possibility that activation of ADAM17 by oncogenic forms of Src can aid in promoting tumorigenesis by enhancing signaling via the EGFR and ERK in an autocrine and paracrine manner. Enhanced autocrine signaling could further activate tumor cells expressing oncogenic mutants of Src, whereas paracrine signaling could stimulate EGFR and ERK signaling in surrounding non-transformed cells such as stromal cells, thereby contributing to crosstalk between tumor cells and stromal cells.

Cirrhosis develops from liver fibrosis and is the severe pathological stage of all chronic liver injury. Cirrhosis caused by hepatitis B virus and hepatitis C virus infection is especially common. Liver fibrosis and cirrhosis involve excess production of extracellular matrix, which is closely related to liver sinusoidal endothelial cells (LSECs). Damaged LSECs can synthesize transforming growth factor-beta and platelet-derived growth factor, which activate hepatic stellate cells and facilitate the synthesis of extracellular matrix. Herein, we highlight the angiogenic cytokines of LSECs related to liver fibrosis and cirrhosis at different stages and focus on the formation and development of liver fibrosis and cirrhosis. Inhibition of LSEC angiogenesis and antiangiogenic therapy are described in detail. Targeting LSECs has high therapeutic potential for liver diseases. Further understanding of the mechanism of action will provide stronger evidence for the development of anti-LSEC drugs and new directions for diagnosis and treatment of liver diseases.