Xiukun Lin

Role of MicroRNA-26b in Glioma Development and Its Mediated Regulation on EphA2

Background MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of multiple target genes. Deregulation of miRNAs is common in human tumorigenesis. Low level expression of miR-26b has been found in glioma cells. However, its underlying mechanism of action has not been determined. Methodology/Principal Findings Real-time PCR was employed to measure the expression level of miR-26b in glioma patients and cells. The level of miR-26b was inversely correlated with the grade of glioma. Ectopic expression of miR-26b inhibited the proliferation, migration and invasion of human glioma cells. A binding site for miR-26b was identified in the 3′UTR of EphA2. Over-expression of miR-26b in glioma cells repressed the endogenous level of EphA2 protein. Vasculogenic mimicry (VM) experiments were performed to further confirm the effects of miR-26b on the regulation of EphA2, and the results showed that miR-26b inhibited the VM processes which regulated by EphA2. Significance This study demonstrated that miR-26b may act as a tumor suppressor in glioma and it directly regulates EphA2 expression. EphA2 is a direct target of miR-26b, and the down-regulation of EphA2 mediated by miR-26b is dependent on the binding of miR-26b to a specific response element of microRNA in the 3′UTR region of EphA2 mRNA.

Bromophenols in Marine Algae and Their Bioactivities

Marine algae contain various bromophenols that have been shown to possess a variety of biological activities, including antioxidant, antimicrobial, anticancer, anti-diabetic, and anti-thrombotic effects. Here, we briefly review the recent progress of these marine algal biomaterials, with respect to structure, bioactivities, and their potential application as pharmaceuticals.

Antitumor Peptides from Marine Organisms

The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new antitumor agents in the field of the development of marine bioactive substances. In this review, the progress on studies of antitumor peptides from marine sources is provided. The biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is also presented. Novel peptides that induce apoptosis signal pathway, affect the tubulin-microtubule equilibrium and inhibit angiogenesis are presented in association with their pharmacological properties. It is intended to provide useful information for further research in the fields of marine antitumor peptides.

miR-125b regulates the proliferation of glioblastoma stem cells by targeting E2F2

microRNAs (miRNAs) play important role in regulating cancer stem cell self‐renewal and differentiation, but the expression prolife of miRNAs in glioma stem cells (GSCs) has not been addressed. Here, we found that CD133 positive GSCs possess a unique miRNAs profile compared to CD133 negative glioblastoma cells. miR‐125b, as one of neuronal miRNAs, is the most significantly down‐regulated miRNAs and overexpression of miR‐125b inhibits the proliferation of CD133 positive GSCs and reduces the expression of “stem” marker. Furthermore, two binding sites for miR‐125b are identified in the 3′UTR of E2F2 and overexpression of miR‐125b in CD133 positive GSCs represses the endogenous level of E2F2 protein. This study demonstrated that miR‐125b plays important roles in regulating the proliferation of GSCs by directly targeting E2F2.

Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells.

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits potential anti‐tumor activity against many tumor cell lines. This study aims to examine the anti‐tumor activity of OA on pancreatic cancer cells and its potential molecular mechanism. The results showed that the proliferation of Panc‐28 cells was inhibited by OA in a concentration‐dependent manner, with an IC50 (The half maximal inhibitory concentration) value of 46.35 µg ml−1, as determined by MTT (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay. The cell cycle was arrested in S phase and G2/M phase by OA. The study also showed that OA could induce remarkable apoptosis, evidenced by an increased percentage of early/late apoptotic cells, DNA ladder and nuclear morphology change. Further study revealed that OA could induce Reactive Oxygen Species (ROS) generation, mitochondrial depolarization, release of cytochrome C, lysosomal membrane permeabilization and leakage of cathepin B. The expression of apoptosis‐correlated proteins was also affected in cells treated with OA, including activation of caspases‐3/9 and cleavage of PARP. Further study confirmed that ROS scavenger vitamin C could reverse the apoptosis induced by OA in Panc‐28 cells. Our results provide evidence that OA arrests the cell cycle and induces apoptosis, possibly via ROS‐mediated mitochondrial and a lysosomal pathway in Panc‐28 cells. Copyright

Translational autoregulation of thymidylate synthase and dihydrofolate reductase.

The folate-dependent enzymes, thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are critical for providing the requisite nucleotide precursors for maintaining DNA synthesis and DNA repair. In addition to their essential roles in enzyme catalysis, these two enzymes have now been shown to function as RNA binding proteins. Using in vitro and in vivo experimental model systems, we have shown that the functional consequence of binding of TS protein to its own cognate mRNA, as well as binding of DHFR to its own DHFR mRNA, is translational repression. Herein, we review and update studies focusing on the translational autoregulatory control of TS and DHFR expression and discuss the molecular elements that are required for these specific RNA-protein interactions. Moreover, we present evidence showing that abrogation of these normal translational autoregulatory feedback mechanisms provides the molecular basis for the rapid development of cellular drug resistance.

Synthesis and α-glucosidase inhibitory mechanisms of bis(2,3-dibromo-4,5-dihydroxybenzyl) ether, a potential marine bromophenol α-glucosidase inhibitor.

Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE), derived from the marine algae, is a potential α-glucosidase inhibitor for type 2 diabetes treatment. In the present study, a synthetic route was established as a valid approach to obtain BDDE. Fluorescence spectra, circular dichroism spectra and molecular docking methods were employed to elucidate the inhibitory mechanisms of BDDE against α-glucosidase. The results showed that BDDE could be prepared effectively and efficiently with the established synthetic methods. Synthetic BDDE bound with α-glucosidase and induced minor conformational changes of the enzyme. The docking results indicated the interaction between BDDE and α-glucosidase was driven by both hydrophobic forces and hydrogen bonds. The docked BDDE molecule was completely buried in the α-glucosidase binding pocket with part of the molecule reaching the catalytic center and overlapping with the position of glucose, and the rest of the molecule extending towards protein surface. This study provides useful information for the understanding of the BDDE-α-glucosidase interaction and for the development of novel α-glucosidase inhibitors.

Oleanolic Acid Suppresses Aerobic Glycolysis in Cancer Cells by Switching Pyruvate Kinase Type M Isoforms

Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents.

Targeting Cellular Proapoptotic Molecules for Developing Anticancer Agents from Marine Sources

Apoptosis as a form of programmed cell death is a critical defense mechanism against the formation and progression of cancer and exhibits distinct morphological and biochemical traits. In an in vivo situation, apoptosis functions to eliminate potentially deleterious cells without causing such adverse effects as inflammatory response and ensuing scar formation. Therefore, targeting apoptotic pathways becomes an intriguing strategy for the development of chemotherapeutic agents. Marine natural products have become an important source in the discovery of antitumor drugs, especially when modern technology makes it more and more feasible to collect organisms from seas. Although lack of an analog of a long ethno-medical history for finding clues, as compared with terrestrial habitats, still hinders the progress, an increasing number of compounds have been isolated from marine organisms that have been found to possess apoptosis-inducing and anticancer activities. This primer summarizes several such compounds, based on their effects on apoptotic signaling pathways, although most of these products have not yet been studied in depth for their mechanisms of action.

Targeting cellular apoptotic pathway with peptides from marine organisms

Apoptosis is a critical defense mechanism against the formation and progression of cancer and exhibits distinct morphological and biochemical traits. Targeting apoptotic pathways becomes an intriguing strategy for the development of chemotherapeutic agents. Peptides from marine organisms have become important sources in the discovery of antitumor drugs, especially when modern technology makes it more and more feasible to collect organisms from seas. This primer summarizes several marine peptides, based on their effects on apoptotic signaling pathways, although most of these peptides have not yet been studied in depth for their mechanisms of action. Novel peptides that induce an apoptosis signal pathway are presented in association with their pharmacological properties.