title: Involvement of epigenetics and microRNA-29b in the urethane induced inception and establishment of mouse lung tumors.
abstract: Epigenetic changes are correlated with tumor development showing aberrations in DNA methylation and histone modifications. To find the early changes, we evaluated the epigenetic events from early to late stage of the urethane induced lung tumor development in mouse model and tried to correlate the molecular events with the progression of tumor. We addressed the hypothesis by examining the tumor development, status of DNMTs, HDACs and MBDs, DNA methylation and expression of microRNA-29b during 1 to 36 weeks after urethane exposure that included the period before and after the tumor appearance. Tumors did not appear after 1 or 4 weeks but well defined tumors appeared after 12 weeks and larger tumors appeared at 36 weeks which was prevented by IP6. DNMT1, DNMT3a and DNMT3b were upregulated after urethane exposure at the time of no tumor till the tumor developed and showed its upregulated functional activity. DNMTs are shown to be the targets of microRNA-29b and we showed that microRNA-29b was downregulated in the line of DNMT upregulation. HDAC, the histone modifier, also showed progressive upregulation. Periodic increase in methyl binding proteins, MBD2, supported the expression of gene silencing pathways in terms of the downregulation of tumor suppressor genes, p16 and MLH1. All these molecular alterations were protected in the presence of IP6. Our results showed that the key steps of epigenetics, DNMTs, mir29b, and HDAC1, are altered both before and after the development of tumors.
authors.affiliation: Environmental Carcinogenesis Division, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow 226001, India.
authors.forename: Manuraj
authors.initials: M
authors.lastname: Pandey
authors.affiliation: Dept. of Medical Elementology and Toxicology, Jamia Hamdard, Hamdard Nagar, New Delhi, India.
authors.forename: Sarwat
authors.initials: S
authors.lastname: Sultana
authors.affiliation: Environmental Carcinogenesis Division, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow 226001, India. Electronic address: krishnag522@yahoo.co.in.
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Gupta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014520:Urethane / Q000633:toxicity*; D000097584:DNA Methyltransferase 3B
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins; D056284:Histone Deacetylase 1; D035683:MicroRNAs; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014520:Urethane; D000097584:DNA Methyltransferase 3B; C417743:Cdkn2a protein, mouse; C000715535:Dnmt3a protein, mouse; C547014:MIRN29 microRNA, mouse; C489326:Mbd2 protein, mouse; C501485:Mlh1 protein, mouse; C068271:inositol hexakisphosphate receptor; C000619381:Dnmt1 protein, mouse; C484389:Hdac1 protein, mouse
keywords: DNA methylation; DNMTs; Epigenetics; HDAC1; Lung cancer; MicroRNA-29b