1 miR-17-5p is overexpressed in hepatocellular carcinoma (HCC), but the specific regulatory mechanisms of miR-17-5p in HCC remain unknown. We investigated the molecular basis of miR-17-5p as an oncogene in human HCC cell lines. Our in vivo and in vitro data indicate that miR-17-5p up-regulates the migration and proliferation of HCC cells. Interestingly, proteomic and western blotting assays revealed that miR-17-5p significantly activates the p38 mitogen-activated protein kinase MAPK pathway and increases the phosphorylation of heat shock protein 27 (HSP27). Our results also suggest that E2F1-dependent down-regulation of Wip1 regulates miR-17-5p-p38-HSP27 signaling. Furthermore, suppression of HSP27 expression by small interfering RNA or the p38 MAPK pathwayspecific inhibitor SB203580 decreases the migration of HCC cells overexpressing miR-17-5p but does not reduce their proliferation. Finally, we show that miR-17-5p expression correlates well with HSP27 status in primary human HCC tissues with metastasis. Conclusion: Our findings suggest that the p38 MAPK pathway plays a crucial role in miR-17-5p-induced phosphorylation of HSP27 and, as a consequence, phosphorylated HSP27 enhances the migration of HCC cells. Our data highlight an important role of miR-17-5p in the proliferation and migration of HCC cells and support the potential application of miR-17-5p in HCC therapy. (HEPATOLOGY 2010;51:1614-1623 M icroRNAs (miRNAs) are 21-to 25-nucleotide RNA molecules that regulate cellular differentiation, apoptosis, proliferation, and migration.1,2 Many studies have shown that miRNAs are implicated in many cancers, and altered miRNA levels can result in the aberrant expression of gene products that may contribute to cancer biology.3,4 Indeed, some miRNAs have been classified as tumor suppressors or oncogenes.5 Recent studies that have used hybridization-based microarrays to investigate miRNA expression profiles in human hepatocellular carcinoma (HCC) have identified nonoverlapping signatures of a small number of miRNAs that are up-regulated and downregulated in human HCC compared with paired peritumoral tissues.6-8 Although the roles of miRNAs in HCC have recently been postulated, their pathophysiological contributions to HCC are still largely unknown.The miR-17-92 cluster (composed of miR-17-5p, miR-17-3p, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92-1) first attracted attention following a series of observations linking these miRNAs to cancer pathogenesis.9 Overexpression of the miR-17-92 locus has been identified in lung cancer, 10 B cell lymphoma, 9 HCC, 11 and stomach solid tumors. 12 Moreover, elevated expression of the miR-17-92 polycistron in hepadnavirus-associated HCC contributes to a malignant phenotype. 13 The association of miR-17-92Abbreviations: DIGE, differential in-gel electrophoresis; HCC, hepatocellular carcinoma; HSP27, heat shock protein 27; MAPK, mitogen-activated protein kinase; miRNA, microRNA; MMP-2, matrix metalloproteinase 2; siRNA, small interfering RNA.From the

The loss of microRNA-122 (miR-122) expression correlates to many characteristic properties of hepatocellular carcinoma (HCC) cells, including clonogenic survival, anchorage-independent growth, migration, invasion, epithelial-mesenchymal transition, and tumorigenesis. However, all of these findings do not sufficiently explain the oncogenic potential of miR-122. In the current study, we used two-dimensional differential in-gel electrophoresis to measure changes in the expression of thousands of proteins in response to the inhibition of miR-122 in human hepatoma cells. Several proteins that were upregulated on miR-122 inhibition were involved in the unfolded protein response (UPR) pathway. The overexpression of miR-122 resulted in the repression of UPR pathway activation. Therefore, miR-122 may act as an inhibitor of the chaperone gene expression and negatively regulate the UPR pathway in HCC. We further showed that the miR-122 inhibitor enhanced the stability of the 26S proteasome non-ATPase regulatory subunit 10 (PSMD10) through the up-regulation of its target gene cyclin-dependent kinase 4 (CDK4). This process may activate the UPR pathway to prevent chemotherapy-mediated tumor cell apoptosis. The current study suggests that miR-122 negatively regulates the UPR through the CDK4-PSMD10 pathway. The down-regulation of miR-122 activated the CDK4-PSMD10-UPR pathway to decrease tumor cell anticancer drug-mediated apoptosis. We identified a new HCC therapeutic target and proclaimed the potential risk of the therapeutic use of miR-122 silencing.

Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1–3 (HNP1–3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information.

Chronic hepatitis B (CHB) appears to progress more rapidly in males than in females, and CHB-related hepatic cirrhosis and hepatocellular carcinoma are predominately diseases that tend to occur in men and postmenopausal women. To obtain more insight into the underlying mechanisms of gender disparity of CHB progress, two-dimensional difference gel electrophoresis was employed to compare liver proteome of C57BL/6 and HBV transgenic (HBV-Tg) mice both in male and female groups. We identified 8 differently expressed proteins in male HBV-Tg mice and 12 in female HBV-Tg mice. Apolipoprotein A-I (Apo A-I) was found to be down-regulated in male and female HBV-Tg mouse liver. It is more interesting that the pattern of liver Apo A-I isoforms was altered in male HBV-Tg mice but not in female HBV-Tg mice. Our further results indicated that the basic Apo A-I isoform, based on pI positions from serum 2-dimensional Western blotting, increased in male CHB patient sera but not in female CHB patient sera. Finally, we identified that the oxidative modification Apo A-I mainly reside in basic isoform. This pattern of selectively modified Apo A-I isoforms may be considered as a pathological hallmark that may extend our knowledge of the molecular pathogenesis of CHB progression.

The concept of Industry 4.0 has been widely recognized by the world since its introduction in 2011 Hannover Industrial Expo. Industry 4.0 strategy does not only revolutionize the manufacturing system and processes but also lead to the formation of the intelligent supply chain. Currently, Industry 4.0‐based intelligent supply chain has attracted a lot of attention from academia; however, studies on performance measurement indicator of intelligent supply chain are still lacking. To fill this gap, this paper first introduces the impact of Industry 4.0 on supply chain management. After analysing key characteristics of intelligent supply chain, the paper proposes a performance measurement indicator framework consisting of seven indicators. This indicator framework enriches the theoretical knowledge of supply chain performance evaluation and provides an efficient way to improve the operational performance of intelligent supply chain management.