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Identification of Rtl1,a Retrotransposon-Derived Imprinted Gene,as a Novel Driver of Hepatocarcinogenesis
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نویسنده
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riordan j.d. ,keng v.w. ,tschida b.r. ,scheetz t.e. ,bell j.b. ,podetz-pedersen k.m. ,moser c.d. ,copeland n.g. ,jenkins n.a. ,roberts l.r. ,largaespada d.a. ,dupuy a.j.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 4
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چکیده
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We previously utilized a sleeping beauty (sb) transposon mutagenesis screen to discover novel drivers of hcc. this approach identified recurrent mutations within the dlk1-dio3 imprinted domain,indicating that alteration of one or more elements within the domain provides a selective advantage to cells during the process of hepatocarcinogenesis. for the current study,we performed transcriptome and small rna sequencing to profile gene expression in sb-induced hccs in an attempt to clarify the genetic element(s) contributing to tumorigenesis. we identified strong induction of retrotransposon-like 1 (rtl1) expression as the only consistent alteration detected in all sb-induced tumors with dlk1-dio3 integrations,suggesting that rtl1 activation serves as a driver of hcc. while previous studies have identified correlations between disrupted expression of multiple dlk1-dio3 domain members and hcc,we show here that direct modulation of a single domain member,rtl1,can promote hepatocarcinogenesis in vivo. overexpression of rtl1 in the livers of adult mice using a hydrodynamic gene delivery technique resulted in highly penetrant (86%) tumor formation. additionally,we detected overexpression of rtl1 in 30% of analyzed human hcc samples,indicating the potential relevance of this locus as a therapeutic target for patients. the rtl1 locus is evolutionarily derived from the domestication of a retrotransposon. in addition to identifying rtl1 as a novel driver of hcc,our study represents one of the first direct in vivo demonstrations of a role for such a co-opted genetic element in promoting carcinogenesis. © 2013 riordan et al.
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آدرس
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department of anatomy and cell biology,roy j. and lucille a. carver college of medicine,university of iowa,iowa city,ia, United States, masonic cancer center,department of genetics,cell biology and development and center for genome engineering,university of minnesota,minneapolis,mn,united states,department of applied biology and chemical technology,the hong kong polytechnic university,hung hom,kowloon, Hong Kong, masonic cancer center,department of genetics,cell biology and development and center for genome engineering,university of minnesota,minneapolis,mn, United States, center for bioinformatics and computational biology,department of opthalmology and visual sciences,roy j. and lucille a. carver college of medicine,university of iowa,iowa city,ia, United States, department of genetics,cell biology and development and center for genome engineering,university of minnesota,minneapolis,mn, United States, department of genetics,cell biology and development and center for genome engineering,university of minnesota,minneapolis,mn, United States, division of gastroenterology and hepatology,college of medicine,mayo clinic and mayo clinic cancer center,rochester,mn, United States, cancer research program,the methodist hospital research institute,houston,tx, United States, cancer research program,the methodist hospital research institute,houston,tx, United States, division of gastroenterology and hepatology,college of medicine,mayo clinic and mayo clinic cancer center,rochester,mn, United States, masonic cancer center,department of genetics,cell biology and development and center for genome engineering,university of minnesota,minneapolis,mn, United States, department of anatomy and cell biology,roy j. and lucille a. carver college of medicine,university of iowa,iowa city,ia, United States
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Authors
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