miR-183 regulates autophagy and apoptosis in colorectal cancer through targeting of UVRAG

Ultraviolet radiation resistance-associated gene (UVRAG) is a well-known regulator of autophagy by promoting autophagosome formation and maturation. Multiple studies have implicated UVRAG in the pathogenesis of colorectal cancer. However, the mechanisms underlying the regulation of UVRAG are unclear. Here, we describe miR-183 as a new autophagy-inhibiting miRNA. Our results showed that induction of autophagy lead to down-regulation of miR-183 in colorectal cancer cells. And, over-expression of miR-183 resulted in the attenuation of rapamycin- or starvation-induced autophagy in cancer cells, whereas inhibition of endogenous miR-183 stimulated autophagy and apoptosis. Additionally, either autophagy inhibitor 3-MA or pan-caspase inhibitor Z-VAD-FMK respectively or both treatments reversed AMO-183-induced cell death. Further studies showed that UVRAG is a target of miR-183 and as a key regulator promotes autophagy and apoptosis. More importantly, over-expression of UVRAG rescued autophagic activity and induced apoptosis in presence of miR-183. Therefore, the present study investigated the promoting effect of miR-183 on colorectal cancer progression, which was considered to be mediated by autophagy and apoptosis through targeting of UVRAG.

[1]  M. Diederich,et al.  Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target. , 2015, Biochemical pharmacology.

[2]  N. Petrelli,et al.  A review of the evolution of systemic chemotherapy in the management of colorectal cancer. , 2015, Clinical colorectal cancer.

[3]  How-Ran Guo,et al.  Arsenic trioxide induces programmed cell death through stimulation of ER stress and inhibition of the ubiquitin-proteasome system in human sarcoma cells. , 2015, Cancer letters.

[4]  Jacob Rosenberg,et al.  Colorectal carcinogenesis--update and perspectives. , 2014, World journal of gastroenterology.

[5]  Michael N. Hall,et al.  mTORC1 mediated translational elongation limits intestinal tumour initiation and growth , 2014, Nature.

[6]  Shiaoching Gong,et al.  Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex , 2014, PLoS genetics.

[7]  H. Ling,et al.  MicroRNAs as novel predictive biomarkers and therapeutic targets in colorectal cancer. , 2014, World journal of gastroenterology.

[8]  Dan Yan,et al.  MicroRNA-183 inhibits gastric cancer proliferation and invasion via directly targeting Bmi-1 , 2014, Oncology letters.

[9]  C. Isidoro,et al.  Expression and Clinical Significance of the Autophagy Proteins BECLIN 1 and LC3 in Ovarian Cancer , 2014, BioMed research international.

[10]  F. Sinicrope,et al.  Beclin 1 and UVRAG Confer Protection from Radiation-Induced DNA Damage and Maintain Centrosome Stability in Colorectal Cancer Cells , 2014, PloS one.

[11]  B. Liu,et al.  Oncogenic and tumor suppressive roles of microRNAs in apoptosis and autophagy , 2014, Apoptosis.

[12]  X. Wen,et al.  Oncogenic and tumor suppressive roles of microRNAs in apoptosis and autophagy , 2014, Apoptosis.

[13]  Carlo Follo,et al.  Epigenetic Control of Autophagy by MicroRNAs in Ovarian Cancer , 2014, BioMed research international.

[14]  P. Panda,et al.  Autophagy and apoptosis: where do they meet? , 2014, Apoptosis.

[15]  P. Panda,et al.  Autophagy and apoptosis: where do they meet? , 2014, Apoptosis.

[16]  Donna D. Zhang,et al.  The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death , 2013, Autophagy.

[17]  Haizhu Song,et al.  MicroRNA-mediated autophagic signaling networks and cancer chemoresistance. , 2013, Cancer biotherapy & radiopharmaceuticals.

[18]  Qinghe Zhang,et al.  Meta-analysis of microRNA-183 family expression in human cancer studies comparing cancer tissues with noncancerous tissues. , 2013, Gene.

[19]  T. P. Neufeld,et al.  ULK1 induces autophagy by phosphorylating Beclin-1 and activating Vps34 lipid kinase , 2013, Nature Cell Biology.

[20]  R. Dahiya,et al.  microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer , 2013, British Journal of Cancer.

[21]  R. Agami,et al.  MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 , 2013, Autophagy.

[22]  Xuejun Jiang,et al.  The ULK1 complex , 2013, Autophagy.

[23]  Duojiao Ni,et al.  UVRAG: at the crossroad of autophagy and genomic stability. , 2012, Autophagy.

[24]  D. Rubinsztein,et al.  Autophagy modulation as a potential therapeutic target for diverse diseases , 2012, Nature Reviews Drug Discovery.

[25]  A. Lund,et al.  MicroRNA regulation of autophagy. , 2012, Carcinogenesis.

[26]  Bo Liu,et al.  MicroRNA-modulated autophagic signaling networks in cancer. , 2012, The international journal of biochemistry & cell biology.

[27]  C. Plass,et al.  miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells. , 2012, Cancer research.

[28]  D. Tang,et al.  A critical role for UVRAG in apoptosis , 2011, Autophagy.

[29]  N. Miller,et al.  MicroRNAs in colorectal cancer: function, dysregulation and potential as novel biomarkers. , 2011, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[30]  D. Tang,et al.  UV irradiation resistance‐associated gene suppresses apoptosis by interfering with BAX activation , 2011, EMBO reports.

[31]  A. Gill,et al.  MicroRNA Profiling of Sporadic and Hereditary Medullary Thyroid Cancer Identifies Predictors of Nodal Metastasis, Prognosis, and Potential Therapeutic Targets , 2011, Clinical Cancer Research.

[32]  Jun Yu,et al.  MicroRNA in colorectal cancer: from benchtop to bedside. , 2011, Carcinogenesis.

[33]  K. Liestøl,et al.  A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic. , 2010, Experimental cell research.

[34]  Subbaya Subramanian,et al.  MicroRNA miR-183 functions as an oncogene by targeting the transcription factor EGR1 and promoting tumor cell migration. , 2010, Cancer research.

[35]  M. Bjørås,et al.  Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein. , 2010, Blood.

[36]  N. Mizushima,et al.  Methods in Mammalian Autophagy Research , 2010, Cell.

[37]  D. Klionsky,et al.  Regulation mechanisms and signaling pathways of autophagy. , 2009, Annual review of genetics.

[38]  B. Levine,et al.  The autophagy effector Beclin 1: a novel BH3-only protein , 2008, Oncogene.

[39]  G. Kroemer,et al.  Autophagic cell death: the story of a misnomer , 2008, Nature Reviews Molecular Cell Biology.

[40]  Jae U. Jung,et al.  Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking , 2008, Nature Cell Biology.

[41]  J. J. Mul,et al.  Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis , 2007, Nature Cell Biology.

[42]  W. Hung,et al.  Arsenic salts induced autophagic cell death and hypermethylation of DAPK promoter in SV-40 immortalized human uroepithelial cells. , 2007, Toxicology letters.

[43]  Thomas Lengauer,et al.  A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 , 2007, Nature Genetics.

[44]  Chengyu Liang,et al.  UVRAG: A New Player in Autophagy and Tumor Cell Growth , 2007, Autophagy.

[45]  B. Oh,et al.  Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG , 2006, Nature Cell Biology.

[46]  S. Markowitz,et al.  Manipulation of nonsense mediated decay identifies gene mutations in colon cancer Cells with microsatellite instability , 2004, Oncogene.

[47]  T. Goi,et al.  Ascending Colon Cancer with Hepatic Metastasis and Cholecystolithiasis in a Patient with Situs Inversus Totalis Without Any Expression of UVRAG mRNA: Report of a Case , 2003, Surgery Today.

[48]  N. Thornberry,et al.  Inhibition of Human Caspases by Peptide-based and Macromolecular Inhibitors* , 1998, The Journal of Biological Chemistry.

[49]  R. Agami,et al.  © 2012 Landes Bioscience. Do not distribute. miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1 , 2012 .

[50]  E. Morselli,et al.  Control of autophagy by oncogenes and tumor suppressor genes , 2009, Cell Death and Differentiation.

[51]  A. Meijer,et al.  The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. , 1997, European journal of biochemistry.