title: Differentiation therapy for hepatocellular carcinoma: Multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis.
abstract: The death rate from hepatocellular carcinoma (HCC) is increasing, and liver cancer is the second leading cause of cancer-related mortality worldwide. Most patients with HCC have underlying liver cirrhosis and compromised liver function, limiting treatment options. Cirrhosis is associated with cell dedifferentiation and expansion of hepatocholangiolar progenitor cells. We identified a microRNA signature associated with HCC and hepatocytic differentiation of progenitor cells. We further identified miR-148a as an inducer of hepatocytic differentiation that is down-regulated in HCC. MiR-148a-mimetic treatment in vivo suppressed tumor growth, reduced tumor malignancy and liver fibrosis, and prevented tumor development. These effects were associated with an increased differentiated phenotype and mediated by IκB kinase alpha/NUMB/NOTCH signaling.
  
  
  CONCLUSIONS
  miR-148a is an inhibitor of the IκB kinase alpha/NUMB/NOTCH pathway and an inducer of hepatocytic differentiation that when deregulated promotes HCC initiation and progression. Differentiation-targeted therapy may be a promising strategy to treat and prevent HCC.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Kwang Hwa
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Department of Experimental Therapeutics and the Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of Experimental Therapeutics and the Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Gynecologic and Reproductive Oncology and the Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Laura
authors.initials: L
authors.lastname: Beretta
mesh_terms: D000818:Animals; D001552:Benzazepines; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005355:Fibrosis; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D010641:Phenotype; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism; D005466:Fluorocarbons
chemical_list: D001552:Benzazepines; D015415:Biomarkers; D051550:I-kappa B Kinase; D035683:MicroRNAs; D051880:Receptors, Notch; C550570:MIRN148 microRNA, human; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons