Molecular Pathogenesis of Preeclampsia: MicroRNA Hypothesis

The discovery of micro RNA (miRNA) in 1993 by Ambros and colleagues has a huge influence in pathogenesis theory, diagnosis and treatment approach of some diseases. Some studies have conducted to seek the association alterations of miRNA expression to incidences and severity of preeclampsia (PE). We have reviewed some studies that conducted to seek the association of miRNA and PE and we discussed the role of various miRNAs in PE pathogenesis. In summary, we have shown that many researchers have given evident that the different placental and plasma miRNA expression is associated with PE. Some studies also identified the novel candidate of miRNAs (and their pathways) that may be of etiologic relevance in the pathogenesis of PE. Base on review, specific miRNA have a role to down regulate of anti apoptosis genes, regulate angiogenics growth factors such as angiogenin, vascular endothelial growth factor (VEGF) B (VEGF-β), cysteine-rich 61 (CYR61), Placental growth factor (PlGF) and VEGF-A that have a role in angiogenesis. miRNA also have a role in survival, migration, and capillary tube formation of HUVEC by targeted of c-kit. Some miRNAs target genes that participate in immunologic dysfunction, cell adhesion, cell cycle, and signaling. miRNA also have a roles in endothelial cell response to hypoxia, cell differentiation, and survival. A miRNA influence calcium signaling through negative regulations of the calmodulin-coding mRNAs, Mef2a and Gata4, mainly in smooth muscle cells that contribute to PE pathogenesis. These investigations provide novel targets for further investigation of the pathogenesis of PE and these differential miRNAs may be potential markers for the diagnosis and provide a potential therapeutic target for PE. Further investigations on posttranscriptional regulation in PE to evaluate biologic effects of identified miRNAs (including confirmations of miRNA and target gene interactions) are neede

Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance

Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers.Val Skinner FoundationNational Institutes of Health (U.S.) (RC1 CA147961)Rutgers Cancer Institute of New JerseyRutgers Cancer Institute of New Jersey (P30 CA072720)National Institutes of Health (U.S.) (R01 CA163591)National Institutes of Health (U.S.) (R37 CA53370)National Institutes of Health (U.S.) (R01 CA130893

Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells

Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7(−/−)) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival