STAT3 can be activated through paracrine signaling in breast epithelial cells

<p>Abstract</p> <p>Background</p> <p>Many cancers, including breast cancer, have been identified with increased levels of phosphorylated or the active form of Signal Transducers and Activators of Transcription 3 (STAT3) protein. However, whether the tumor microenvironment plays a role in this activation is still poorly understood.</p> <p>Methods</p> <p>Conditioned media, which contains soluble factors from MDA-MB-231 and MDA-MB-468 breast cancer cells and breast cancer associated fibroblasts, was added to MCF-10A breast epithelial and MDA-MB-453 breast cancer cells. The stimulation of phosphorylated STAT3 (p-STAT3) levels by conditioned media was assayed by Western blot in the presence or absence of neutralized IL-6 antibody, or a JAK/STAT3 inhibitor, JSI-124. The stimulation of cell proliferation in MCF-10A cells by conditioned media in the presence or absence of JSI-124 was subjected to MTT analysis. IL-6, IL-10, and VEGF levels were determined by ELISA analysis.</p> <p>Results</p> <p>Our results demonstrated that conditioned media from cell lines with constitutively active STAT3 are sufficient to induce p-STAT3 levels in various recipients that do not possess elevated p-STAT3 levels. This signaling occurs through the JAK/STAT3 pathway, leading to STAT3 phosphorylation as early as 30 minutes and is persistent for at least 24 hours. ELISA analysis confirmed a correlation between elevated levels of IL-6 production and p-STAT3. Neutralization of the IL-6 ligand or gp130 was sufficient to block increased levels of p-STAT3 (Y705) in treated cells. Furthermore, soluble factors within the MDA-MB-231 conditioned media were also sufficient to stimulate an increase in IL-6 production from MCF-10A cells.</p> <p>Conclusion</p> <p>These results demonstrate STAT3 phosphorylation in breast epithelial cells can be stimulated by paracrine signaling through soluble factors from both breast cancer cells and breast cancer associated fibroblasts with elevated STAT3 phosphorylation. The induction of STAT3 phosphorylation is through the IL-6/JAK pathway and appears to be associated with cell proliferation. Understanding how IL-6 and other soluble factors may lead to STAT3 activation via the tumor microenvironment will provide new therapeutic regimens for breast carcinomas and other cancers with elevated p-STAT3 levels.</p

Mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) cause 1.6% of autosomal dominant retinitis pigmentosa

Purpose: The purpose of this project was to determine the spectrum and frequency of mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) that cause autosomal dominant retinitis pigmentosa (adRP). Methods: A well-characterized adRP cohort of

Highly anomalous accumulation rates of C and N recorded by a relic, free-floating peatland in Central Italy

Floating islands mysteriously moving around on lakes were described by several Latin authors almost two millennia ago. These fascinating ecosystems, known as free-floating mires, have been extensively investigated from ecological, hydrological and management points of view, but there have been no detailed studies of their rates of accumulation of organic matter (OM), organic carbon (OC) and total nitrogen (TN). We have collected a peat core 4 m long from the free-floating island of Posta Fibreno, a relic mire in Central Italy. This is the thickest accumulation of peat ever found in a free-floating mire, yet it has formed during the past seven centuries and represents the greatest accumulation rates, at both decadal and centennial timescale, of OM (0.63 vs. 0.37 kg/m2/yr), OC (0.28 vs. 0.18 kg/m2/yr) and TN (3.7 vs. 6.1 g/m2/yr) ever reported for coeval peatlands. The anomalously high accretion rates, obtained using 14C age dating, were confirmed using 210Pb and 137Cs: these show that the top 2 m of Sphagnum-peat has accumulated in only ~100 years. As an environmental archive, Posta Fibreno offers a temporal resolution which is 10x greater than any terrestrial peat bog, and promises to provide new insight into environmental changes occurring during the Anthropocene