Details

Autor(en) / Beteiligte

• Santhekadur, Prasanna K.
• Gredler, Rachel
• Chen, Dong
• Siddiq, Ayesha
• Shen, Xue-Ning
• Das, Swadesh K.
• Emdad, Luni
• Fisher, Paul B.
• Sarkar, Devanand

Titel

Late SV40 Factor (LSF) Enhances Angiogenesis by Transcriptionally Up-regulating Matrix Metalloproteinase-9 (MMP-9)

Ist Teil von

• The Journal of biological chemistry, 2012-01, Vol.287 (5), p.3425-3432

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• The transcription factor late SV40 factor (LSF) is overexpressed in human hepatocellular carcinoma (HCC) fostering a highly aggressive and metastatic phenotype. Angiogenesis is an essential component of cancer aggression and metastasis and HCC is a highly aggressive and angiogenic cancer. In the present studies, we analyzed the molecular mechanism of LSF-induced angiogenesis in HCC. Employing human umbilical vein endothelial cells (HUVEC) differentiation assay and chicken chorioallantoic membrane (CAM) assay we document that stable LSF overexpression augments and stable dominant negative inhibition of LSF (LSFdn) abrogates angiogenesis by human HCC cells. A quest for LSF-regulated factors contributing to angiogenesis, by chromatin immunoprecipitation-on-chip (ChIP-on-chip) assay, identified matrix metalloproteinase-9 (MMP-9) as a direct target of LSF. MMP-9 expression and enzymatic activity were higher in LSF-overexpressing cells and lower in LSFdn-expressing cells. Deletion mutation analysis identified the LSF-responsive regions in the MMP-9 promoter and ChIP assay confirmed LSF binding to the MMP-9 promoter. Inhibition of MMP-9 significantly abrogated LSF-induced angiogenesis as well as in vivo tumorigenesis, thus reinforcing the role of MMP-9 in facilitating LSF function. The present findings identify a novel target of LSF contributing to its oncogenic properties. Background: The transcription factor Late SV40 Factor (LSF) is overexpressed in human hepatocellular carcinoma (HCC). Results: LSF augments tumor angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9). Conclusion: A novel target of LSF is identified contributing to its oncogenic properties. Significance: LSF regulates a network of proteins, including osteopontin, MMP-9, and c-Met, thereby establishing the rationale for LSF inhibition as a potential therapeutic strategy for HCC.