Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that both canine and human OSA cell lines, as well as 8 fresh canine OSA tumor samples, exhibit constitutive phosphorylation of STAT3, and that this correlates with enhanced expression of matrix metalloproteinase-2 (MMP2). While multiple signal transduction pathways can result in phosphorylation of STAT3, stimulation of the cytokine receptor gp130 through either IL-6 or Oncostatin M (OSM) is the most common mechanism through which STAT3 is activated. The purpose of this study was to evaluate the role of IL-6 and OSM stimulation on both canine and human OSA cell lines to begin to determine the role of these cytokines in the biology of OSA.</p> <p>Methods</p> <p>RT-PCR and Western blotting were used to interrogate the consequences of OSM and IL-6 stimulation of OSA cell lines. OSA cells were stimulated with OSM and/or hepatocyte growth factor (HGF) and the effects on MMP2 activity (gel zymography), proliferation (CyQUANT), invasion (Matrigel transwell assay), and VEGF production (Western blotting, ELISA) were assessed. The small molecule STAT3 inhibitor LLL3 was used to investigate the impact of STAT3 inhibition following OSM stimulation of OSA cells.</p> <p>Results</p> <p>Our data demonstrate that the OSM receptor (OSMR), but not IL-6 or its receptor, is expressed by all human and canine OSA cell lines and canine OSA tumor samples; additionally, OSM expression was noted in all tumor samples. Treatment of OSA cell lines with OSM induced phosphorylation of STAT3, Src, and JAK2. OSM stimulation also resulted in a dose dependent increase in MMP2 activity and VEGF expression that was markedly reduced following treatment with the small molecule STAT3 inhibitor LLL3. Lastly, OSM stimulation of OSA cell lines enhanced invasion through Matrigel, particularly in the presence of rhHGF. In contrast, both OSM and HGF stimulation of OSA cell lines did not alter their proliferative capacity.</p> <p>Conclusions</p> <p>These data indicate OSM stimulation of human and canine OSA cells induces STAT3 activation, thereby enhancing the expression/activation of MMP2 and VEGF, ultimately promoting invasive behavior and tumor angiogenesis. As such, OSM and its receptor may represent a novel target for therapeutic intervention in OSA.</p

Systematic review of beliefs, behaviours and influencing factors associated with disclosure of a mental health problem in the workplace

Stigma and discrimination present an important barrier to finding and keeping work for individuals with a mental health problem. This paper reviews evidence on: 1) employment-related disclosure beliefs and behaviours of people with a mental health problem; 2) factors associated with the disclosure of a mental health problem in the employment setting; 3) whether employers are less likely to hire applicants who disclose a mental health problem; and 4) factors influencing employers' hiring beliefs and behaviours towards job applicants with a mental health problem

Bicaudal D induces selective dynein-mediated microtubule minus end-directed transport

Bicaudal D is an evolutionarily conserved protein, which is involved in dynein-mediated motility both in Drosophila and in mammals. Here we report that the N–terminal portion of human Bicaudal D2 (BICD2) is capable of inducing microtubule minus end-directed movement independently of the molecular context. This characteristic offers a new tool to exploit the relocalization of different cellular components by using appropriate targeting motifs. Here, we use the BICD2 N–terminal domain as a chimera with mitochondria and peroxisome-anchoring sequences to demonstrate the rapid dynein-mediated transport of selected organelles. Surprisingly, unlike other cytoplasmic dynein-mediated processes, this transport shows very low sensitivity to overexpression of the dynactin subunit dynamitin. The dynein-recruiting activity of the BICD2 N–terminal domain is reduced within the full-length molecule, indicating that the C–terminal part of the protein might regulate the interaction between BICD2 and the motor complex. Our findings provide a novel model system for dissection of the molecular mechanism of dynein motility

An SP1-like transcription factor Spr2 acts downstream of Fgf signaling to mediate mesoderm induction

Fgf signaling, mediated in part by the transcription factor Brachyury/Xbra/Ntl, plays important roles in mesoderm formation during the early development of vertebrate embryos. We have identified a zebrafish gene, spr2, which encodes a member of the Sp1-like transcription factor family. spr2 is expressed in both hypoblast and epiblast cells during late blastulation/early gastrulation, and in some mesodermal and neural tissues at later stages. Injection with spr2 mRNA enhances ntl expression and alleviates the inhibitory effect on ntl of XFD, a Xenopus dominant-negative FGF receptor. In contrast, morpholino- mediated knockdown of Spr2 activity inhibits ntl expression and reduces the inductive effect of Fgfs on ntl. We also demonstrate that Fgf signaling relays mesoderm induction activity of Nodal signaling and Spr2 is involved in this signal relay process. Furthermore, the correct spatial expression of spr2 requires Nodal, Fgf and Wnt signals. We suggest that expression of spr2 is an immediate-early response to mesoderm induction by Fgfs, which in turn regulates the expression of effector genes involved in the development of mesodermal tissues