Durand, T. | bioRxiv Science

bioRxiv2019

Hepatitis C virus regulates its replication by maturing miR-122 through Akt-dependent phosphorylation of KSRP

The liver-specific micro-RNA-122 (miR-122) is required for the replication of hepatitis C virus (HCV). The direct interaction between miR-122 and the 5 untranslated region of the HCV genome promotes viral replication and protects HCV RNA from degradation. Because HCV RNA is its own substrate for replication, infected cells are submitted to the sequestration of increasing levels of miR-122 and to global de-repression of host miR-122 mRNA targets. Whether and how HCV regulates miR-122 maturation to create an environment favorable to its replication remains unexplored. We discovered that Akt-dependent phosphorylation of KSRP host protein at Serine residue 193 is essential for miR-122 maturation in hepatocytes. Moreover, we showed the existence of a reciprocal regulation loop where HCV replication can modulate the proviral effect mediated by KSRP-dependent maturation of miR-122. These data support a mechanism by which HCV regulates the expression of miR-122 by hijacking KSRP, thereby fueling its own replication.

microbiology↗

bioRxiv2019

Oxidized products of α-linolenic acid negatively regulate cellular survival and motility of breast cancer cells

BackgroundCancer is a major cause of death in the world, and more than six million new cases are reported every year. Despite recent advances in our understanding of the biological processes leading to the development and progression of cancer, there is still a need for new and effective agents to treat this disease. Phytoprostanes (PhytoPs) and phytofurans (PhytoFs) are non-enzymatically oxidized products of -linolenic acid that are present in seeds and vegetable oils. They have been shown to possess anti-inflammatory and apoptosis-promoting activities in macrophages and leukemia cells, respectively.\n\nMethodsIn this work, seven PhytoPs (PP1-PP7) and one PhytoFs (PF1) were evaluated for their cytotoxic, chemosensitization and anti-migratory activities using the MCF-7 and MDA-MB-231 breast cancer cell lines.\n\nResultsAmong the compounds tested, only three PhytoPs had a significant effect on cell viability compared to the control group: Ent-9-L1-PhytoP (PP6) decreased cell viability in both cell lines, while 16-F1t-PhytoP (PP1) and 9-L1-PhytoP (PP5) decreased viability in MCF-7 and MDA-MB-231 cells, respectively. When combined with a sub-cytotoxic dose of doxorubicin, these three PhytoPs significantly enhanced the cytotoxic effect on MCF-7 cells while the chemotherapeutic drug alone had no effect. In cellular motility assays, Ent-9-(RS)-12-epi-ST-{Delta}10-13-PhytoF could significantly inhibit cellular migration of MDA-MB-231 cells in a wound-healing and a transwell assays. In addition, Ent-9-(RS)-12-epi-ST-{Delta}10-13-PhytoF also enhanced cellular adhesion of MDA-MB-231 cells.\n\nConclusionsThis study shows for the first time that the plant-derived compounds PhytoPs and PhytoFs could be further exploited alone or in combination with chemotherapy to improve the arsenal of therapies available against breast cancer.

cancer biology↗