title: Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) has the most rapidly rising cancer incidence in the US and Europe. The KLF6 tumor suppressor is frequently inactivated in HCC by loss-of-heterozygosity (LOH) and/or mutation.
  
  
  METHODS
  Here we have analyzed 33 HBV- and 40 HCV-related HCCs for mRNA expression of wildtype KLF6 (wtKLF6) as well as the KLF6 variant 1 (SV1), a truncated, growth-promoting variant that antagonizes wtKLF6 function. The HCV-related tumors analyzed represented the full histologic spectrum from cirrhosis and dysplasia to metastatic cancer.
  
  
  RESULTS
  Expression of KLF6 mRNA is decreased in 73% of HBV-associated HCCs compared to matched surrounding tissue (ST), with reductions of approximately 80% in one-third of the patients. KLF6 mRNA expression is also reduced in dysplastic nodules from patients with HCV compared to cirrhotic livers (p<0.005), with an additional, marked decrease in the very advanced, metastatic stage (p<0.05). An increased ratio of KLF6SV1/wt KLF6 is present in a subset (6/33, 18%) of the HBV-related HCCs compared to matched ST. Reconstituting KLF6 in HepG2 cells by retroviral infection decreased proliferation and related markers including cyclin D1 and beta-catenin, increased cellular differentiation based on induction of albumin, E-cadherin, and decreased alpha fetoprotein.
  
  
  CONCLUSIONS
  We conclude that reduced KLF6 expression is common in both HBV- and HCV-related HCCs and occurs at critical stages during cancer progression. Effects of KLF6 are attributable to regulation of genes controlling hepatocyte growth and differentiation.
authors.affiliation: Division of Liver Diseases and Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Sigal
authors.initials: S
authors.lastname: Kremer-Tal
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.forename: Yingbei
authors.initials: Y
authors.lastname: Chen
authors.forename: Eldad
authors.initials: E
authors.lastname: Hod
authors.forename: Analisa
authors.initials: A
authors.lastname: DiFeo
authors.forename: Steven
authors.initials: S
authors.lastname: Yea
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Myron
authors.initials: M
authors.lastname: Schwartz
authors.forename: Swan N
authors.initials: SN
authors.lastname: Thung
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Fiel
authors.forename: Michaela
authors.initials: M
authors.lastname: Banck
authors.forename: Eran
authors.initials: E
authors.lastname: Zimran
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000556:secondary / Q000821:virology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D018014:Gene Transfer Techniques; D014644:Genetic Variation; D006509:Hepatitis B / Q000150:complications; D006526:Hepatitis C / Q000150:complications; D006525:Hepatitis, Viral, Human / Q000150:complications*; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism
chemical_list: D015415:Biomarkers; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012367:RNA, Viral