The calcium binding protein S100 family in humans contains 21 known members, with each possessing a molecular weight between 10 and 14 kDa. These proteins are characterized by a unique helix-loop-helix EF hand motif, and often form dimers and multimers. The S100 family mainly exists in vertebrates and exerts its biological functions both inside cells as a calcium sensor/binding protein, as well as outside cells. S100A11, a member of the S100 family, may mediate signal transduction in response to internal or external stimuli and it plays various roles in different diseases such as cancers, metabolic disease, neurological diseases, and vascular calcification. In addition, it can function as chemotactic agent in inflammatory disease. In this review, we first detail the discovery of S100 proteins and their structural features, and then specifically focus on the tissue and organ expression of S100A11. We also summarize its biological activities and roles in different disease and signaling pathways, providing an overview of S100A11 research thus far.

Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. We performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The autophagy and lipogenesis were detected in vitro and in vivo by Western blot and quantitative polymerase chain reaction. The functions of SIRT1, histone deacetylase 6 (HDAC6), and FOXO1 were inhibited by specific inhibitors. The interactions between related proteins were analyzed by a co-immunoprecipitation assay and immunofluorescence analysis. The expression of S100A11 was up-regulated significantly in a time-dependent manner in the tree shrew model of NAFLD. S100A11 expression was induced consistently in oleic acid-treated liver cells as well as the livers of mice fed a high-fat diet and NAFLD patients. Both in vitro and in vivo overexpression of S100A11 could induce hepatic lipid accumulation. Mechanistically, overexpression of S100A11 activated an autophagy and lipogenesis process through up-regulation and acetylation of the transcriptional factor FOXO1, consequently promoting lipogenesis and lipid accumulation in vitro and in vivo. Inhibition of HDAC6, a deacetylase of FOXO1, showed similar phenotypes to S100A11 overexpression in Hepa 1-6 cells. S100A11 interacted with HDAC6 to inhibit its activity, leading to the release and activation of FOXO1. Under S100A11 overexpression, the inhibition of FOXO1 and autophagy could alleviate the activated autophagy as well as up-regulated lipogenic genes. Both FOXO1 and autophagy inhibition and Dgat2 deletion could reduce liver cell lipid accumulation significantly. A high-fat diet promotes liver S100A11 expression, which may interact with HDAC6 to block its binding to FOXO1, releasing or increasing the acetylation of FOXO1, thus activating autophagy and lipogenesis, and accelerating lipid accumulation and liver steatosis. These findings indicate a completely novel S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and liver steatosis, providing potential possibilities for the treatment of NAFLD.

Hepatic stellate cells (HSCs), previously described for liver‐specific mesenchymal stem cells (MSCs), appear to contribute to liver regeneration. Microvesicles (MVs) are nanoscale membrane fragments, which can regulate target cell function by transferring contents from their parent cells. The aim of this study was to investigate the effect of HSC‐derived MVs on xenobiotic‐induced liver injury. Rat and human hepatocytes, BRL‐3A and HL‐7702, were used to build hepatocytes injury models by n‐acetyl‐p‐aminophenol n‐(APAP) or H₂O₂ treatment. MVs were prepared from human and rat HSCs, LX‐2, and HST‐T6 and, respectively, added to injured BRL‐3A and HL‐7702 hepatocytes. MTT assay was utilized to determine cell proliferation. Cell apoptosis was analyzed by flow cytometry and hoechst33258 staining. Western blot was used for analyzing the expression of activated caspase‐3. Liver injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in culture medium were also assessed. Results showed that (1) HSC‐MVs derived from LX‐2 and HST‐T6 were positive to CD90 and annexin V surface markers; (2) HSC‐MVs dose‐dependently improved the viability of hepatocytes in both injury models; (3) HSC‐MVs dose‐dependently inhibited the APAP/H₂O₂ induced hepatocytes apoptosis and activated caspase‐3 expression and leakage of LDH, ALT, and AST. Our results demonstrate that HSC‐derived MVs protect hepatocytes from toxicant‐induced injury.

Previous studies have shown that forkhead box P4 antisense RNA 1 (FOXP4‐AS1) is dysregulated in tumor tissues and can serve as a prognostic indicator for multiple cancers. However, the clinical significance of FOXP4‐AS1 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The goal of this study is to recognize the possible clinical significance of long noncoding RNA FOXP4‐AS1 in patients with early stage PDAC. A total of 112 patients from The Cancer Genome Atlas (TCGA) PDAC cohort, receiving RNA sequencing, were involved in the study. Survival analysis, functional mechanism, and potential small molecule drugs of target therapy of FOXP4‐AS1 were performed in this study. Survival analysis in TCGA PDAC cohort suggested that patients with high FOXP4‐AS1 expression had significantly augmented possibility of death than in PDAC patients with lower FOXP4‐AS1 expression (adjusted P = .008; adjusted HR = 2.143, 95% CI = 1.221‐3.760). In this study, a genome‐wide RNA sequencing dataset was used to identify 927 genes co‐expressing with FOXP4‐AS1 in PDAC tumor tissues. A total of 676 differentially expressed genes were identified between different FOXP4‐AS1 expression groups. Functional enrichment analysis of these genes and gene set enrichment analysis for PDAC genome‐wide RNA sequencing dataset was done. We have found that FOXP4‐AS1 may function in PDAC by participating in biological processes and pathways including oxidative phosphorylation, tricarboxylic acid cycle, classical tumor‐related pathways such as NF‐kappaB as well as Janus kinase/signal transducers in addition to activators of transcription, cell proliferation, and adhesion. In addition, we also screened two potential targeted therapeutic small molecule drugs (dimenhydrinate and metanephrine) for FOXP4‐AS1 in PDAC. In conclusion, our present study demonstrated that higher expression of FOXP4‐AS1 in PDAC tumor tissues were related with an inferior medical outcome. Through multiple genome‐wide approaches, we identified the potential molecular mechanisms of FOXP4‐AS1 in PDAC and two targeted therapeutic drugs for it.

BACKGROUND There are few effective tools to predict survival in patients with invasive intraductal papillary mucinous neoplasms of the pancreas. AIM To develop comprehensive nomograms to individually estimate the survival outcome of patients with invasive intraductal papillary mucinous neoplasms of the pancreas. METHODS Data of 1219 patients with invasive intraductal papillary mucinous neoplasms after resection were extracted from the Surveillance, Epidemiology, and End Results database, and randomly divided into the training (n = 853) and the validation (n = 366) cohorts. Based on the Cox regression model, nomograms were constructed to predict overall survival and cancer-specific survival for an individual patient. The performance of the nomograms was measured according to discrimination, calibration, and clinical utility. Moreover, we compared the predictive accuracy of the nomograms with that of the traditional staging system. RESULTS In the training cohort, age, marital status, histological type, T stage, N stage, M stage, and chemotherapy were selected to construct nomograms. Compared with the American Joint Committee on Cancer 7(th) staging system, the nomograms were generally more discriminative. The nomograms passed the calibration steps by showing high consistency between actual probability and nomogram prediction. Categorial net classification improvements and integrated discrimination improvements suggested that the predictive accuracy of the nomograms exceeded that of the American Joint Committee on Cancer staging system. With respect to decision curve analyses, the nomograms exhibited more preferable net benefit gains than the staging system across a wide range of threshold probabilities. CONCLUSION The nomograms show improved predictive accuracy, discrimination capability, and clinical utility, which can be used as reliable tools for risk classification and treatment recommendations.