title: MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer.
abstract: Hepatocellular carcinoma (HCC) is associated with poor survival for patients and few effective treatment options, raising the need for novel therapeutic strategies. MicroRNAs (miRNAs) play important roles in tumor development and show deregulated patterns of expression in HCC. Because of the liver's unique affinity for small nucleic acids, miRNA-based therapy has been proposed in the treatment of liver disease. Thus, there is an urgent need to identify and characterize aberrantly expressed miRNAs in HCC. In our study, we profiled miRNA expression changes in de novo liver tumors driven by MYC and/or RAS, two canonical oncogenes activated in a majority of human HCCs. We identified an up-regulated miRNA megacluster comprised of 53 miRNAs on mouse chromosome 12qF1 (human homolog 14q32). This miRNA megacluster is up-regulated in all three transgenic liver models and in a subset of human HCCs. An unbiased functional analysis of all miRNAs within this cluster was performed. We found that miR-494 is overexpressed in human HCC and aids in transformation by regulating the G1 /S cell cycle transition through targeting of the Mutated in Colorectal Cancer tumor suppressor. miR-494 inhibition in human HCC cell lines decreases cellular transformation, and anti-miR-494 treatment of primary MYC-driven liver tumor formation significantly diminishes tumor size.
  
  
  CONCLUSIONS
  Our findings identify a new therapeutic target (miR-494) for the treatment of HCC.
authors.affiliation: Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA; Department of Medicine, University of California San Francisco, San Francisco, CA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Lim
authors.forename: Asha
authors.initials: A
authors.lastname: Balakrishnan
authors.forename: Noelle
authors.initials: N
authors.lastname: Huskey
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.forename: Mona
authors.initials: M
authors.lastname: Jodari
authors.forename: Raymond
authors.initials: R
authors.lastname: Ng
authors.forename: Guisheng
authors.initials: G
authors.lastname: Song
authors.forename: Jesse
authors.initials: J
authors.lastname: Riordan
authors.forename: Brittany
authors.initials: B
authors.lastname: Anderton
authors.forename: Siu-Tim
authors.initials: ST
authors.lastname: Cheung
authors.forename: Holger
authors.initials: H
authors.lastname: Willenbring
authors.forename: Adam
authors.initials: A
authors.lastname: Dupuy
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Chang
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
chemical_list: C547168:MIRN494 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; C067857:MCC protein, human; D018631:ras Proteins
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