The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

International audienceHeparan sulfate (HS) proteoglycan chains are key components of the breast tumor microenvironment that critically influence the behavior of cancer cells. It is established that abnormal synthesis and processing of HS play a prominent role in tumorigenesis, albeit mechanisms remain mostly obscure. HS function is mainly controlled by sulfotransferases, and here we report a novel cellular and pathophysiological significance for the 3-O-sulfotransferase 3-OST3A (HS3ST3A), catalyzing the final maturation step of HS, in breast cancer. We show that 3-OST3A is epigenetically repressed in all breast cancer cell lines of a panel representative of distinct molecular subgroups, except in human epidermal growth factor receptor 2-positive (HER2+) sloan-kettering breast cancer (SKBR3) cells. Epigenetic mechanisms involved both DNA methylation and histone modifications, producing different repressive chromatin environments depending on the cell molecular signature. Gain and loss of function experiments by cDNA and siRNA transfection revealed profound effects of 3-OST3A expression on cell behavior including apoptosis, proliferation, response to trastuzumab in vitro and tumor growth in xenografted mice. 3-OST3A exerted dual activities acting as tumor-suppressor in lumA-michigan cancer foundation (MCF)-7 and triple negative-MD Anderson (MDA) metastatic breast (MB)-231 cells, or as an oncogenic factor in HER2+-SKBR3 cells. Mechanistically, fluorescence-resonance energy transfer-fluorescence-lifetime imaging microscopy experiments indicated that the effects of 3-OST3A in MCF-7 cells were mediated by altered interactions between HS and fibroblast growth factor-7 (FGF-7). Further, this interplay between HS and FGF-7 modulated downstream ERK, AKT and p38 cascades, suggesting that altering 3-O-sulfation affects FGFR2IIIb-mediated signaling. Corroborating our cellular data, a clinical study conducted in a cohort of breast cancer patients uncovered that, in HER2+ patients, high level expression of 3-OST3A in tumors was associated with reduced relapse-free survival. Our findings define 3-OST3A as a novel regulator of breast cancer pathogenicity, displaying tumor-suppressive or oncogenic activities in a cell-and tumor-dependent context, and demonstrate the clinical value of the HS-O-sulfotransferase 3-OST3A as a prognostic marker in HER2+ patients

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

Large-Scale Total Water Storage and Water Flux Changes over the Arid and Semiarid Parts of the Middle East from GRACE and Reanalysis Products

© 2016 The Author(s). Previous studies indicate that water storage over a large part of the Middle East has been decreased over the last decade. Variability in the total (hydrological) water flux (TWF, i.e., precipitation minus evapotranspiration minus runoff) and water storage changes of the Tigris–Euphrates river basin and Iran’s six major basins (Khazar, Persian, Urmia, Markazi, Hamun, and Sarakhs) over 2003–2013 is assessed in this study. Our investigation is performed based on the TWF that are estimated as temporal derivatives of terrestrial water storage (TWS) changes from the Gravity Recovery and Climate Experiment (GRACE) products and those from the reanalysis products of ERA-Interim and MERRA-Land. An inversion approach is applied to consistently estimate the spatio-temporal changes of soil moisture and groundwater storage compartments of the seven basins during the study period from GRACE TWS, altimetry, and land surface model products. The influence of TWF trends on separated water storage compartments is then explored. Our results, estimated as basin averages, indicate negative trends in the maximums of TWF peaks that reach up to -5.2 and -2.6 (mm/month/year) over 2003–2013, respectively, for the Urmia and Tigris–Euphrates basins, which are most likely due to the reported meteorological drought. Maximum amplitudes of the soil moisture compartment exhibit negative trends of -11.1, -6.6, -6.1, -4.8, -4.7, -3.8, and -1.2 (mm/year) for Urmia, Tigris–Euphrates, Khazar, Persian, Markazi, Sarakhs, and Hamun basins, respectively. Strong groundwater storage decrease is found, respectively, within the Khazar -8.6 (mm/year) and Sarakhs -7.0 (mm/year) basins. The magnitude of water storage decline in the Urmia and Tigris–Euphrates basins is found to be bigger than the decrease in the monthly accumulated TWF indicating a contribution of human water use, as well as surface and groundwater flow to the storage decline over the study area