title: miR-148a dependent apoptosis of bladder cancer cells is mediated in part by the epigenetic modifier DNMT1.
abstract: Urothelial cell carcinoma of the bladder (UCCB) is the most common form of bladder cancer and it is estimated that ~15,000 people in the United States succumbed to this disease in 2013. Bladder cancer treatment options are limited and research to understand the molecular mechanisms of this disease is needed to design novel therapeutic strategies. Recent studies have shown that microRNAs play pivotal roles in the progression of cancer. miR-148a has been shown to serve as a tumor suppressor in cancers of the prostate, colon, and liver, but its role in bladder cancer has never been elucidated. Here we show that miR-148a is down-regulated in UCCB cell lines. We demonstrate that overexpression of miR-148a leads to reduced cell viability through an increase in apoptosis rather than an inhibition of proliferation. We additionally show that miR-148a exerts this effect partially by attenuating expression of DNA methyltransferase 1 (DNMT1). Finally, our studies demonstrate that treating cells with both miR-148a and either cisplatin or doxorubicin is either additive or synergistic in causing apoptosis. These data taken together suggest that miR-148a is a tumor suppressor in UCCB and could potentially serve as a novel therapeutic for this malignancy.
authors: Department of Medical Microbiology and Immunology, University of California, Davis, California.|Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Group and Biotechnology Program, University of California, Davis, California.|Veterans Affairs-Northern California Health Care System, Mather, California.
authors: Alan P
authors: AP
authors: Lombard
authors: Veterans Affairs-Northern California Health Care System, Mather, California.
authors: Benjamin A
authors: BA
authors: Mooso
authors: Department of Medical Microbiology and Immunology, University of California, Davis, California.|Veterans Affairs-Northern California Health Care System, Mather, California.
authors: Stephen J
authors: SJ
authors: Libertini
authors: Department of Medical Microbiology and Immunology, University of California, Davis, California.
authors: Rebecca M
authors: RM
authors: Lim
authors: Department of Medical Microbiology and Immunology, University of California, Davis, California.
authors: Rachel M
authors: RM
authors: Nakagawa
authors: Department of Medical Microbiology and Immunology, University of California, Davis, California.
authors: Kathleen D
authors: KD
authors: Vidallo
authors: Department of Medical Microbiology and Immunology, University of California, Davis, California.
authors: Nicole C
authors: NC
authors: Costanzo
authors: Veterans Affairs-Northern California Health Care System, Mather, California.|Department of Urology, University of California, Davis, California.
authors: Paramita M
authors: PM
authors: Ghosh
authors: Department of Medical Microbiology and Immunology, University of California, Davis, California.|Veterans Affairs-Northern California Health Care System, Mather, California.
authors: Maria
authors: M
authors: Mudryj
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology*
chemical_list: C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D004317:Doxorubicin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D002945:Cisplatin
keywords: DNA methyltransferase (DNMT1); apoptosis; bladder cancer; cell cycle; cisplatin; doxorubicin; miR-148a