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International audience; Cancer cells are exposed to intrinsic (oncogene) or extrinsic (microenvironmental) challenges, leading to activation of stress response pathways. The unfolded protein response (UPR) is the cellular response to endoplasmic reticulum (ER) stress and plays a pivotal role in tumor development. Depending on ER stress intensity and duration, the UPR is either pro-survival to preserve ER homeostasis or pro-death if the stress cannot be resolved. On one hand, the adaptive arm of the UPR is essential for cancer cells to survive the harsh conditions they are facing, and on the other hand, cancer cells have evolved mechanisms to bypass ER stress-induced cell death, thereby conferring them with a selective advantage for malignant transformation. Therefore, the mechanisms involved in the balance between survival and death outcomes of the UPR may be exploited as therapeutic tools to treat cancer

Steatohepatitis is a cause of hepatocellular carcinoma development; however, the underlying mechanisms are poorly defined. In this issue of Cancer Cell, Nakagawa and colleagues demonstrate that activation of endoplasmic reticulum stress signaling is instrumental in the development of steatohepatitis and synergizes with proinflammatory pathways to promote hepatocarcinogenesis.

The start of university life demands an adaptation period, which can sometimes have an impact on the mental health of students. A total of 233 first year psychology students answered a questionnaire based on a Beck Depression Inventory, Coping Inventory of Stressful Situations, Social Support Questionnaire and Hassles Scale. The results showed 41 per cent of those surveyed suffered of depressive symptoms and that daily hassles encountered during the first year of university could be considered a relevant risk factor for depression. This study makes it possible to observe that not all coping strategies work equally well. Only task-centered, active coping strategies were effective. With many students having to cope with leaving home, social support also plays a fundamental role. In fact, 70 per cent of those interviewed had left their hometown in order to study. The results of this study suggest that depressive symptoms should be considered a significant problem particularly in first year students. Copyright © 2006 John Wiley & Sons, Ltd.

International audience; Hepatocellular carcinoma (HCC) is the major primary liver cancer. Glypican-3 (GPC3), one of the most abnormally expressed genes in HCC, participates in liver carcinogenesis. Based on data showing that GPC3 expression is posttranscriptionally altered in HCC cells compared to primary hepatocytes, we investigated the implication of microRNAs (miRNAs) in GPC3 overexpression and HCC. To identify GPC3-regulating miRNAs, we developed a dual-fluorescence FunREG (functional, integrated, and quantitative method to measure posttranscriptional regulations) system that allowed us to screen a library of 876 individual miRNAs. Expression of candidate miRNAs and that of GPC3 messenger RNA (mRNA) was measured in 21 nontumoral liver and 112 HCC samples. We then characterized the phenotypic consequences of modulating expression of one candidate miRNA in HuH7 cells and deciphered the molecular mechanism by which this miRNA controls the posttranscriptional regulation of GPC3. We identified five miRNAs targeting GPC3 3'-untranslated region (UTR) and regulating its expression about the 876 tested. Whereas miR-96 and its paralog miR-1271 repressed GPC3 expression, miR-129-1-3p, miR-1291, and miR-1303 had an inducible effect. We report that miR-1271 expression is down-regulated in HCC tumor samples and inversely correlates with GPC3 mRNA expression in a particular subgroup of HCC. We also report that miR-1271 inhibits the growth of HCC cells in a GPC3-dependent manner and induces cell death.CONCLUSION:Using a functional screen, we found that miR-96, miR-129-1-3p, miR-1271, miR-1291, and miR-1303 differentially control GPC3 expression in HCC cells. In a subgroup of HCC, the up-regulation of GPC3 was associated with a concomitant down-regulation of its repressor miR-1271. Therefore, we propose that GPC3 overexpression and its associated oncogenic effects are linked to the down-regulation of miR-1271 in HCC.

Introduction:Glioblastoma multiforme (GBM) is the most lethal form of glioma with an overall survival at 5 years nearly null (< 5%). Increasing evidences point towards the RNase activity of IRE1 as a central player in GBM development, particularly in cancer cell invasion, tumor vascularization and recruitment of inflammatory or immune cells. Indeed, IRE1 RNase promotes XBP1 mRNA splicing, a well-described cytoprotective transcription factor that is required for cancer cell survival and this activity also contributes to the degradation of mRNA and microRNA, an activity called RIDD. Recent studies unraveled the presence of somatic mutations on the IRE1 gene in GBM that could play a driver role but without providing any functional information.Results:Here, we have sequenced IRE1 exons in 23 human GBMs and identified a new somatic mutation on the IRE1 gene. Interestingly, using biochemical approaches and an orthotopic tumor graft mouse model we show that this variant displays an altered IRE1 RNase activity. IRE1-dependent gene expression pattern alterations lead to major functional consequences in terms of tumor phenotype including (i) a magnified induction of the inflammatory and pro-angiogenic pathways based on transcriptome signatures from human tumors, (ii) an increase of the aggressiveness/infiltration potential of U87 derived tumors in mice and (iii) the modulation of immune cells recruitment to the tumor.Conclusions:This study provides the first evidence that the selectivity of IRE1 RNase can be modulated naturally and unravels the first mechanistic example of how a somatic mutation in the IRE gene can provide adaptive advantages to glioblastoma cells by reprogramming the tumor stroma.

Drug-induced liver injury (DILI) limits the development and utilization of numerous therapeutic compounds, and consequently presents major challenges to the pharmaceutical industry and clinical medicine1, 2. Acetaminophen (APAP) containing compounds are among the most frequently prescribed drugs, and also the most common cause of DILI3. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and APAP-induced hepatotoxicity. We report that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation, and death. We identified a small molecule inhibitor of Cx32 as a novel hepatoprotectant that achieves the same result in wildtype mice when coadministered with known hepatotoxic drugs. These findings demonstrate that gap junction inhibition is an effective therapy for limiting DILI, and suggest a novel pharmaceutical strategy to improve drug safety.

Objectives CT-scan screening programs for lung cancer detection have been proposed in high-risk subjects, and more recently in former asbestos-exposed subjects. However, to date no data are available on psychological impact of such programs. The aim of this study is to examine the risk factors of psychological distress at baseline of a CT-scan screening program among asbestos-exposed subjects. Methods The Asbestos Post-Exposure Survey (APEXS) was carried out in France between October 2003 and December 2005 in order to screen asbestos-related diseases by CT-scan. Volunteers underwent self-administered questionnaires including an asbestos exposure assessment and, for a large sub-sample, a validated psychological distress scale. Non-exposed subjects were used as reference group. Results At baseline, a significant higher level of distress was observed in exposed subjects (n = 3,122) relative to the reference group (n = 486) after adjustment on age, sex, and tobacco status. This distress is associated independently with the self-perception of (i) intensity of asbestos exposure and (ii) the risk of current or future disease related to the asbestos exposure. The perception of the cancer risk related to asbestos seems to play a fundamental role in this psychological distress. Conclusion In this study, asbestos-exposed subjects experienced a higher significant cancer distress than previously described in literature. These findings may be of potential public health importance. First, the impact of such occupational exposures on quality of life of patients who suffer from cancer related to these exposures has to be appraised. Secondly, the assessment of psychological impact of CT-scan screening programs among asbestos-exposed subjects is also required. Am. J. Ind. Med. 52:288–296, 2009. © 2009 Wiley-Liss, Inc.

Background The aim of this study was to assess the psychological consequences of HRCT scan screening in retired asbestos-exposed workers. Methods A HRCT-scan screening program for asbestos-related diseases was carried out in four regions of France. At baseline (T1), subjects filled in self-administered occupational questionnaires. In two of the regions, subjects also received a validated psychological scale, namely the psychological consequences questionnaire (PCQ). The physician was required to provide the subject with the results of the HRCT scan at a final visit. A second assessment of psychological consequences was performed 6 months after the HRCT-scan examination (T2). PCQ scores were compared quantitatively (t-test, general linear model) and qualitatively (chi²-test, logistic regression) to screening results. Multivariate analyses were adjusted for gender, age, smoking, asbestos exposure and counseling. Results Among the 832 subjects included in this psychological impact study, HRCT-scan screening was associated with a significant increase of the psychological score 6 months after the examination relative to baseline values (8.31 to 10.08, p < 0.0001, t-test). This increase concerned patients with an abnormal HRCT-scan result, regardless of the abnormalities, but also patients with normal HRCT-scans after adjustment for age, gender, smoking status, asbestos exposure and counseling visit. The greatest increase was observed for pleural plaques (+3.60; 95%CI [+2.15;+5.06]), which are benign lesions. Detection of isolated pulmonary nodules was also associated with a less marked but nevertheless significant increase of distress (+1.88; 95%CI [+0.34;+3.42]). However, analyses based on logistic regressions only showed a close to significant increase of the proportion of subjects with abnormal PCQ scores at T2 for patients with asbestosis (OR = 1.92; 95%CI [0.97-3.81]) or with two or more diseases (OR = 2.04; 95%CI [0.95-4.37]). Conclusion This study suggests that HRCT-scan screening may be associated with increased distress in asbestos-exposed subjects. If confirmed, these results may have consequences for HRCT-scan screening recommendations.