SUMMARY Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharide lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo, and conferred a T helper 1 (Th1) cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection and cancer.

Objective Curcumin is an active extract from turmeric. The aim of this study was to identify the underlying mechanism of curcumin on PCa cells and the role of autophagy in this process. Methods The inhibitory effect of curcumin on the growth of PANC1 and BxPC3 cell lines was detected by CCK-8 assay. Cell cycle distribution and apoptosis were tested by flow cytometry. Autophagosomes were tested by cell immunofluorescence assay. The protein expression was detected by Western blot. The correlation between LC3II/Bax and cell viability was analyzed. Results Curcumin inhibited the cell proliferation in a dose- and time-dependent manner. Curcumin could induce cell cycle arrest at G2/M phase and apoptosis of PCa cells. The autophagosomes were detected in the dosing groups. Protein expression of Bax and LC3II was upregulated, while Bcl2 was downregulated in the high dosing groups of curcumin. There was a significant negative correlation between LC3II/Bax and cell viability. Conclusions Autophagy could be triggered by curcumin in the treatment of PCa. Apoptosis and cell cycle arrest also participated in this process. These findings imply that curcumin is a multitargeted agent for PCa cells. In addition, autophagic cell death may predominate in the high concentration groups of curcumin.

The microRNA (miR)‐29 family is closely associated with fibrotic processes by virtue of its low expression in many tissues during organ fibrosis. The present study investigated whether miR‐29b overexpression suppressed hepatic stellate cell (HSC) activation and its interactions with transforming growth factor (TGF)‐β1/mothers against decapentaplegic homolog 3 (Smad3), a classical signal transduction pathway contributing to the activation of HSCs. The results showed that transfection of LX‐2 (human HSC) cells with miR‐29b mimic or pSUPER‐Smad3 silencing (si)RNA resulted in significantly increased expression of miR‐29b and decreased expression of Smad3. miR‐29b overexpression inhibited proliferation of LX‐2 cells 24 h after transfection. Both miR‐29b overexpression and Smad3 silencing antagonized the effects of TGF‐β1 on the expression of α‐smooth muscle actin (α‐SMA) and collagen type I (col‐1). Furthermore, infection with miR‐29b mimics suppressed Smad3 and TGF‐β1 expression, suggesting that miR‐29b inhibited LX‐2 activation mediated by both Smad3 and TGF‐β1. Nevertheless, primary miR‐29a/b1, miR‐29b2/c and mature miR‐29b were downregulated by TGF‐β1 and stimulated by Smad3 silencing, suggesting that TGF‐β1/Smad3 signalling pathway regulate not just mature miR‐29b but also its transcription. In summary, our results show overwhelming evidence corroborating the suppressive effect of miR‐29b on TGF‐β1‐induced LX‐2 cell activation. The results also revealed the existence of crosstalk between miR‐29b and TGF‐β1/Smad3 during LX‐2 activation, suggesting a feedback loop between miR‐29b and TGF‐β1/Smad3 signalling that promotes liver fibrosis. Copyright © 2016 The Authors. Cell Biochemistry and Function published by John Wiley & Sons, Ltd.

Ferroptosis is a regulated cell death nexus linking metabolism, redox biology and diseases including cancer. The aim of the present study was to identify a ferroptosis-related gene prognostic signature for pancreatic cancer (PCa) by systematic analysis of transcriptional profiles from Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). Altogether 14 ferroptosis-relevant genes with potential prognostic values were identified, based on which a risk score formula was constructed. According to the risk scores, we classified the patients into a high- and a low-risk score group. It was verified in Gene Expression Omnibus (GEO) and ICGC (International Cancer Genome Consortium) datasets. The Kaplan-Meier survival curves demonstrated that patients with lower risk scores had significantly favorable overall survival (OS) (P < 0.0001). The area under the receiver operating curve (ROC) for 12, 18 and 24 months was about 0.8 in all patients. The result of immune status analysis revealed that the signature significantly associated with the immune infiltration and immune checkpoint blockade (ICB) proteins. In addition, we used quantitative real time PCR (q-rtPCR) and Human Protein Atlas (HPA) to validate the expression of the key genes. Collectively, the signature is valuable for survival prediction of PCa patients. As the signature also has relevance with the immune characteristics, it may help improve the efficacy of personalized immunotherapy.