Volume 400, Issue 8

The role of proteases in cancer was originally thought to be limited to the breakdown of basement membranes and extracellular matrix (ECM), thereby promoting cancer cell invasion into surrounding normal tissues. It is now well understood that proteases play a much more complicated role in all stages of cancer progression and that not only tumor cells, but also stromal cells are an important source of proteases in the tumor microenvironment. Among all the proteolytic enzymes potentially associated with cancer, some proteases have taken on heightened importance due to their significant up-regulation and ability to participate at multiple stages of cancer progression and metastasis. In this review, we discuss some of the advances in understanding of the roles of several key proteases from different classes in the development and progression of cancer and the potential to leverage their upregulated activity for the development of novel targeted treatment strategies.

During oxidative and nitrosative stress conditions cellular organelles convey information to the nucleus to express specific sets of genes to withstand the stress condition and to reorganize their growth and developmental pattern. This organelle to nucleus communication is termed retrograde signaling. In the plant system chloroplast and peroxisomes are mainly involved with little involvement of mitochondria and other organelles in oxidative stress-mediated retrograde signaling. In this review, we will discuss retrograde signaling in plant systems with factors that regulate this signaling cascade.

The prevalence of obesity and its co-morbidities such as insulin resistance and type 2 diabetes are tightly linked to increased ingestion of palatable fat enriched food. Thus, it seems intuitive that the brain senses elevated amounts of fatty acids (FAs) and affects adaptive metabolic response, which is connected to mitochondrial function and insulin signaling. This review will address the effect of dietary FAs on brain insulin and mitochondrial function with a special emphasis on the impact of different FAs on brain function and metabolism.

The striatin-interacting phosphatases and kinases (STRIPAK) complex is evolutionary highly conserved and has been structurally and functionally described in diverse lower and higher eukaryotes. In recent years, this complex has been biochemically characterized better and further analyses in different model systems have shown that it is also involved in numerous cellular and developmental processes in eukaryotic organisms. Further recent results have shown that the STRIPAK complex functions as a macromolecular assembly communicating through physical interaction with other conserved signaling protein complexes to constitute larger dynamic protein networks. Here, we will provide a comprehensive and up-to-date overview of the architecture, function and regulation of the STRIPAK complex and discuss key issues and future perspectives, linked with human diseases, which may form the basis of further research endeavors in this area. In particular, the investigation of bi-directional interactions between STRIPAK and other signaling pathways should elucidate upstream regulators and downstream targets as fundamental parts of a complex cellular network.

The role of Zn 2+ -sensing receptor GPR39 on glucose homeostasis and incretin regulation was assessed in enteroendocrine L- and K-cells. Anti-hyperglycaemic, insulinotropic and incretin secreting properties of Zn 2+ were explored in normal, diabetic and incretin receptor knockout mice. Compared to intraperitoneal injection, oral administration of Zn 2+ (50 μmol/kg body weight) with glucose (18 mmol/kg) in lean mice reduced the glycaemic excursion by 25–34% ( p  < 0.05– p  < 0.001) and enhanced glucose-induced insulin release by 46–48% ( p  < 0.05– p  < 0.01). In diabetic mice, orally administered Zn 2+ lowered glucose by 24–31% ( p  < 0.01) and augmented insulin release by 32% ( p  < 0.01). In glucagon like peptide-1 (GLP-1) receptor knockout mice, Zn 2+ reduced glucose by 15–28% ( p  < 0.05– p  < 0.01) and increased insulin release by 35–43% ( p  < 0.01). In contrast Zn 2+ had no effect on responses of glucose-dependent insulinotropic polypeptide (GIP) receptor knockout mice. Consistent with this, Zn 2+ had no effect on circulating total GLP-1 whereas GIP release was stimulated by 26% ( p  < 0.05) in lean mice. Immunocytochemistry demonstrated GPR39 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Zn 2+ had a direct effect on GIP secretion from pGIPneo STC-1 cells, increasing GIP secretion by 1.3-fold. GPR39 is expressed on intestinal L- and K-cells, and stimulated GIP secretion plays an integral role in mediating enhanced insulin secretion and glucose tolerance following oral administration of Zn 2+ . This suggests development of potent and selective GPR39 agonists as a therapeutic approach for diabetes.

Despite the advance of diagnosis and treatment for prostate cancer, the prognosis of metastatic prostate cancer is poor. We aimed to explore the functional role of long non-coding RNA cardiac hypertrophy-related factor (lncRNA CHRF) in prostate cancer cells (PC3) as well as the molecular mechanisms. LncRNA CHRF silence repressed cell number (%), down-regulated expression of cyclinD1, CDK4 and CDK6, and promoted apoptosis along with activation of the casapse-3 and caspase-9. LncRNA CHRF promoted mesenchymal transition (EMT), showing down-regulation of E-cadherin and up-regulation of N-cadherin, vimentin and ZEB1. Afterwards, we found miR-10b expression was positively correlated with lncRNA CHRF expression, and miR-10b inhibition could reverse the effects of lncRNA CHRF on PC3 and LNCaP cell proliferation and EMT. Finally, lncRNA CHRF was found to activate the GSK3β/AKT and NF-κB pathways via up-regulation of miR-10b. LncRNA CHRF silence repressed proliferation and EMT while promoted apoptosis in PC3 cells via positive regulation of miR-10b. The GSK3β/AKT and NF-κB pathways were activated by lncRNA CHRF, possibly through up-regulation of miR-10b.

The aim of this study was to investigate whether long non-coding RNA (lncRNA) DYNLRB2-2 can inhibit foam cell formation by activating autophagy. The location of DYNLRB2-2 in THP-1-derived macrophages was analyzed by fluorescence in situ hybridization (FISH). Oxidized-low-density lipoprotein (ox-LDL) was used to induce the formation of foam cells, Oil Red O (ORO) staining and high-performance liquid chromatography (HPLC) were performed to detect accumulation of lipid droplets and the level of cholesterol concentration, respectively. The mRNA and protein level of ATP-binding cassette transporter A1 (ABCA1) were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. Relative protein levels of (p-) liver kinase B1 (LKB1), (p-) AMP-activated protein kinase (AMPK), (p-) the mammalian target of rapamycin (mTOR) and autophagy markers (LC3 II, Beclin-1 and p62) in THP-1 macrophage-derived foam cells were analyzed by Western blotting. The levels of inflammatory factors [tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β] in THP-1 macrophage-derived foam cells were detected by enzyme-linked immunosorbent assay (ELISA). 3-MA and compound C were used to block autophagy. Our data show that DYNLRB2-2 inhibited the formation of THP-1 macrophage-derived foam cells and promotes cholesterol efflux (CE) by activating autophagy. DYNLRB2-2 caused autophagy by activating the signaling pathway of LKB1/AMPK/mTOR in foam cells. DYNLRB2-2 activated the LKB1/AMPK/mTOR signaling pathway via the miR-298/Sirtuin 3 (SIRT3) axis. Our data indicated that DYNLRB2-2 enhanced CE by regulating the LKB1/AMPK/mTOR autophagy signaling pathway through the miR-298/SIRT3 axis, thereby blocking the formation of foam cells from THP-1 macrophages.

Pancreatitis is a disease caused by inflammation of pancreatic acinar cells. Geniposide (GEN) possesses anti-inflammation activities. Hence, we investigated the effects of GEN on lipopolysaccharide (LPS)-stimulated AR42J cells. AR42J cells were stimulated by LPS and then treated with GEN and/or transfected with miR-27a mimic or negative control. Cell viability and cell apoptosis were detected using the Cell Counting Kit-8 and flow cytometry, respectively. All related proteins were measured by Western blot. The expression of miR-27a was detected by quantitative real time-polymerase chain reaction (qRT-PCR). Moreover, the expression of inflammatory cytokines interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP)-1 was analyzed by qRT-PCR and Western blot. LPS significantly decreased cell viability, and enhanced cell apoptosis and IL-6, MCP-1 expression. Then GEN administration alleviated inflammatory injury by increasing cell viability, while reducing apoptosis, and IL-6 and MCP-1 expression. GEN downregulated miR-27a expression which was induced by LPS. Transfection with miR-27a mimic partially eliminated the protective effects of GEN. The phosphorylation of JNK and c-Jun was downregulated by GEN while upregulated by miR-27a overexpression. GEN alleviates LPS-induced AR42J cell injury as evidenced by promoting cell growth, and upregulation of IL-6 and MCP-1. This process might be modulated by down-regulating miR-27a and inactivation of JNK pathway.

Breast cancer is the most commonly diagnosed cancer in women worldwide. Tripterine is an important active component isolated from Triperygium wilfordii Hook F. This study investigated the effects of tripterine on breast cancer cell proliferation, migration, invasion and apoptosis, as well as microRNA-15a (miR-15a) expression. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to measure the expression of miR-15a. Cell transfection was conducted to change the expression of miR-15a. Viability, proliferation, migration, invasion and apoptosis of MDA-MB-231 cells were assessed using the cell counting kit-8 (CCK-8) assay, BrdU incorporation assay, Annexin V-FITC/PI apoptosis detection kit and two-chamber Transwell assay, respectively. Expression of key factors involving in cell proliferation, migration, invasion and apoptosis, as well as the PI3K/AKT and JNK pathways, were evaluated using Western blotting. We found that tripterine inhibited MDA-MB-231 cell viability, proliferation, migration and invasion, but induced cell apoptosis. Moreover, tripterine up-regulated the expression of miR-15a in a concentration-dependent manner and miR-15a participated in the effects of tripterine on MDA-MB-231 cell proliferation, migration, invasion and apoptosis. In addition, tripterine inactivated PI3K/AKT and JNK pathways in MDA-MB-231 cells by up-regulating miR-15a. In conclusion, tripterine inhibited proliferation, migration and invasion of breast cancer MDA-MB-231 cells by up-regulating miR-15a and inactivating PI3K/AKT and JNK pathways.

Vitamin D3 is known to have anticancer actions by affecting tumorigenesis including the cell cycle and cell apoptosis in gastric cancer (GC) cells; the genes including microRNAs (miRNAs) regulated by vitamin D3 signaling remain discovered. miR-99b-3p, the tumor suppressor gene, is not only decreased in GC tissues, but is also induced by vitamin D3 through the vitamin D receptor (VDR) binding on the promoter domain of miR-99b. Further study indicates that miR-99b-3p inhibits cell viability and induces cell arrest in the S-phase in GC cells, the direct target gene of miR-99b-3p is verified to be HoxD3, which is also overexpressed in GC cell lines. Overall, our results show that miR-99b-3p mediates the antiproliferative of vitamin D3 in GC cells and might hold promise for prognosis and therapeutic strategies for GC treatment.