title: Mybl2 expression is under genetic control and contributes to determine a hepatocellular carcinoma susceptible phenotype.
abstract: OBJECTIVE
  MYBL2 is implicated in human malignancies and over expressed in hepatocellular carcinoma (HCC). We investigated Mybl2 role in the acquisition of susceptibility to HCC and tumor progression.
  
  
  METHODS
  MYBL2 mRNA and protein levels were evaluated by quantitative RT-PCR and immunoblotting, respectively. MYBL2 expression in HCC cell lines was controlled through MYBL2 cDNA or anti-MYBL2 siRNA transfection. Gene expression profile of cells transfected with MYBL2 was analyzed by microarray.
  
  
  RESULTS
  Low induction of Mybl2 and its target Clusterin mRNAs, in low-grade dysplastic nodules (DN), progressively increased in fast growing high-grade DN and HCC of F344 rats, susceptible to hepatocarcinogenesis, whereas no/lower increases occurred in slow growing lesions of resistant BN rats. Highest Mybl2 protein activation, prevalently nuclear, occurred in F344 than BN lesions. Highest Mybl2, Clusterin, Cdc2, and Cyclin B1 expression occurred in fast progressing DN and HCC of E2f1 transgenics, compared to c-Myc transgenics, and anti-Mybl2 siRNA had highest anti-proliferative and apoptogenic effects in cell lines from HCC of E2f1 transgenics. MYBL2 transfected HepG2 and Huh7 cells exhibited increased cell proliferation and G1-S and G2-M cell cycle phases. The opposite occurred when MYBL2 was silenced by specific siRNA. MYBL2 transfection in Huh7 cells led to upregulation of genes involved in signal transduction, cell proliferation, cell motility, and downregulation of oncosuppressor and apoptogenic genes.
  
  
  CONCLUSIONS
  mybl2 expression and activation are under genetic control. Mybl2 upregulation induces fast growth and progression of premalignant and malignant liver, through cell cycle deregulation and activation of genes and pathways related to tumor progression.
authors.affiliation: Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Frau
authors.forename: Sara
authors.initials: S
authors.lastname: Ladu
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.forename: Maria M
authors.initials: MM
authors.lastname: Simile
authors.forename: Piero
authors.initials: P
authors.lastname: Bonelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Daino
authors.forename: Maria L
authors.initials: ML
authors.lastname: Tomasi
authors.forename: Maria A
authors.initials: MA
authors.lastname: Seddaiu
authors.forename: Francesco
authors.initials: F
authors.lastname: Feo
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pascale
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020570:Genes, myb; D020022:Genetic Predisposition to Disease; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; C493755:E2f1 protein, rat; C064352:MYBL2 protein, human; C499306:Mybl2 protein, mouse; C498883:Mybl2 protein, rat; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors