Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma.

Abstract

PURPOSE:

Hepatocellular carcinoma (HCC) is a highly virulent malignancy with no effective treatment, thus requiring innovative and effective targeted therapies. The oncogene astrocyte-elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis and profoundly downregulates insulin-like growth factor-binding protein-7 (IGFBP7). The present study focuses on analyzing potential tumor suppressor functions of IGFBP7 in HCC and the relevance of IGFBP7 downregulation in mediating AEG-1 function.

EXPERIMENTAL DESIGN:

IGFBP7 expression was detected by immunohistochemistry in HCC tissue microarray and real-time PCR and ELISA in human HCC cell lines. Dual FISH was done to detect LOH at IGFBP7 locus. Stable IGFBP7-overexpressing clones were established in the background of AEG-1-overexpressing human HCC cells and were analyzed for in vitro proliferation and senescence and in vivo tumorigenesis and angiogenesis.

RESULTS:

IGFBP7 expression is significantly downregulated in human HCC samples and cell lines compared with normal liver and hepatocytes, respectively, and inversely correlates with the stages and grades of HCC. Genomic deletion of IGFBP7 was identified in 26% of patients with HCC. Forced overexpression of IGFBP7 in AEG-1-overexpressing HCC cells inhibited in vitro growth and induced senescence, and profoundly suppressed in vivo growth in nude mice that might be an end result of inhibition of angiogenesis by IGFBP7.

CONCLUSION:

The present findings provide evidence that IGFBP7 functions as a novel putative tumor suppressor for HCC and establish the corollary that IGFBP7 downregulation can effectively modify AEG-1 function. Accordingly, targeted overexpression of IGFBP7 might be a potential novel therapy for HCC.

• Authors: Dong Chen, Byoung Kwon Yoo, Prasanna Kumar Santhekadur, Rachel Gredler, Sujit K Bhutia, Swadesh K Das, Christine Fuller, Zao-zhong Su, Paul B Fisher, Devanand Sarkar
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 21 Pg. 6693-701 (Nov 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21908579 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR

Chemical References

• Cell Adhesion Molecules
• Insulin-Like Growth Factor Binding Proteins
• MTDH protein, human
• Membrane Proteins
• RNA-Binding Proteins
• insulin-like growth factor binding protein-related protein 1

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Adhesion Molecules (genetics)
• Cell Line, Tumor
• Chick Embryo
• Chorioallantoic Membrane (blood supply)
• Down-Regulation
• Genes, Tumor Suppressor
• Humans
• Immunohistochemistry
• Insulin-Like Growth Factor Binding Proteins (genetics, metabolism)
• Liver Neoplasms (genetics, metabolism, pathology)
• Loss of Heterozygosity
• Membrane Proteins
• Mice
• Mice, Nude
• Neoplasm Staging
• Neovascularization, Physiologic (genetics)
• RNA-Binding Proteins
• Transplantation, Heterologous