Learning and synaptic plasticity impairments after the first binge drinking episodes in adolescent rats are due to neuroinflammation effects through epigenetic mechanisms

International audienc

Mechanisms of Chronic Alcohol Exposure-Induced Aggressiveness in Cellular Model of HCC and Recovery after Alcohol Withdrawal.

International audienceAlcohol-related liver disease is the most prevalent chronic liver disease worldwide, accounting for 30% of hepatocellular carcinoma (HCC) cases and HCC-specific deaths. However, the knowledge on mechanisms by which alcohol consumption leads to cancer progression and its aggressiveness is limited. Better understanding of the clinical features and the mechanisms of alcohol-induced HCC are of critical importance for prevention and the development of novel treatments. Early stage Huh-7 and advanced SNU449 liver cancer cell lines were subjected to chronic alcohol exposure (CAE), at different doses for 6~months followed by 1-month alcohol withdrawal period. ADH activity and ALDH expression were much lower in SNU449 compared with Huh-7 cells and at the 270~mM dose, CAE decreased cell viability by about 50% and 80%, respectively, in Huh-7 and SNU449 cells but induced mortality only in Huh-7 cells. Thus, Huh-7 may be more vulnerable to ethanol toxicity because of the higher levels of acetaldehyde. CAE induced a dose-dependent increase in cell migration and invasion and also in the expression of cancer stem cells markers (CD133, CD44, CD90). CAE in Huh-7 cells selectively activated ERK1/2 and inhibited GSK3β signaling pathways. Most of the changes induced by CAE were reversed after alcohol withdrawal. Interestingly, we confirmed the increase in CD133 mRNA levels in the tumoral tissue of patients with ethanol-related HCC compared to other HCC etiologies. Our results may explain the benefits observed in epidemiological studies showing a significant increase of overall survival in abstinent compared with non-abstinent patients

Mammary SLAMF3 Regulates Store-Operated Ca2+ Entry and Migration Through STIM1 in Breast Cancer Cells and Cell Lines

International audienceStore Operated Calcium Entry (SOCE) is the main route for calcium entry in breast cells. After it’s activation by STromal Interaction Molecule (STIM) during endoplasmic reticulum store depletion, membrane channels ORAI are the main actors of this cell calcium entry. STIM, ORAI and SOCE alterations might contribute to Breast Cancer (BC) carcinogenesis. Recently, we reported the tumor suppressor role of Signaling Lymphocytic Activation Molecule Family member 3 (SLAMF3) on HepatoCellular Carcinoma (HCC) progression. SLAMF3 has been shown to regulate the activity of immune cells by modulating the calcium influx. In this report, we aimed at exploring the role of SLAMF3 in regulating SOCE and migration of BC cells. We quantified and compared the expression of SLAMF3 and STIM1 by quantitative RT-PCR in tumor and healthy resections of 14 patients followed at the University Hospital of Amiens. The expressions of SLAMF3 and STIM1 were also quantified and compared in non-invasive T47D and invasive MDA-MB-231 cell lines by quantitative RT-PCR, Western blot and flow cytometry. We determined the Ca2+ basal entry as well as SOCE by Mn2+ quenching and calcium imaging, respectively, in T47D and MDA-MB-231 cells overexpressing SLAMF3 ectopically. The cell proliferation and migration/invasion were investigated by MTT, wound healing assay and Boyden chambers tests, respectively. First, we report the expression of SLAMF3 in mammary epithelial cells. We highlight the complete loss of SLAMF3 expression in invasive BC cell lines compared to non-invasive cells. In addition, we show that the forced expression of SLAMF3 in invasive cells down-regulate specifically the STIM1 expression in invasive compared to non-invasive mammary cell lines. Interestingly, an inverse correlation is observed between the low expression of SLAMF3 and the high expression of STIM1 in primary human BC tissues. Our results indicate that SLAMF3 reduces SOCE and therefore restricts BC cell migration by decreasing STIM1 expression. Therefore, SLAMF3 might be used as a predictive marker of BC evolution and aggressiveness