Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a highly aggressive cancer with no currently available effective treatment. Understanding of the molecular mechanism of HCC development and progression is imperative for developing novel, effective, and targeted therapies for this lethal disease. In this article, we document that the cellular transcription factor Late SV40 Factor (LSF) plays an important role in HCC pathogenesis. LSF protein was significantly overexpressed in human HCC cells compared to normal hepatocytes. In 109 HCC patients, LSF protein was overexpressed in >90% cases, compared to normal liver, and LSF expression level showed significant correlation with the stages and grades of the disease. Forced overexpression of LSF in less aggressive HCC cells resulted in highly aggressive, angiogenic, and multiorgan metastatic tumors in nude mice. Conversely, inhibition of LSF significantly abrogated growth and metastasis of highly aggressive HCC cells in nude mice. Microarray studies revealed that as a transcription factor, LSF modulated specific genes regulating invasion, angiogenesis, chemoresistance, and senescence. The expression of osteopontin (OPN), a gene regulating every step in tumor progression and metastasis, was robustly up-regulated by LSF. It was documented that LSF transcriptionally up-regulates OPN, and loss-of-function studies demonstrated that OPN plays an important role in mediating the oncogenic functions of LSF. Together, these data establish a regulatory role of LSF in cancer, particularly HCC pathogenesis, and validate LSF as a viable target for therapeutic intervention.
Yoo
Byoung Kwon
BK
Departments of Human and Molecular Genetics, Virginia Commonwealth University Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Emdad
Luni
L
Gredler
Rachel
R
Fuller
Christine
C
Dumur
Catherine I
CI
Jones
Kimberly H
KH
Jackson-Cook
Colleen
C
Su
Zao-Zhong
ZZ
Chen
Dong
D
Saxena
Utsav H
UH
Hansen
Ulla
U
Fisher
Paul B
PB
Sarkar
Devanand
D
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009857:Oncogenes; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C501906:TFCP2 protein, human; D014157:Transcription Factors; D053495:Osteopontin
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