Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation.
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.
Kremer-Tal
Sigal
S
Division of Liver Diseases and Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Narla
Goutham
G
Chen
Yingbei
Y
Hod
Eldad
E
DiFeo
Analisa
A
Yea
Steven
S
Lee
Ju-Seog
JS
Schwartz
Myron
M
Thung
Swan N
SN
Fiel
Isabel M
IM
Banck
Michaela
M
Zimran
Eran
E
Thorgeirsson
Snorri S
SS
Mazzaferro
Vincenzo
V
Bruix
Jordi
J
Martignetti
John A
JA
Llovet
Josep M
JM
Friedman
Scott L
SL
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
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