Emerging role of insulin-like growth factor-binding protein 7 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a vicious and highly vascular cancer with a dismal prognosis. It is a life-threatening illness worldwide that ranks fifth in terms of cancer prevalence and third in cancer deaths. Most patients are diagnosed at an advanced stage by which time conventional therapies are no longer effective. Targeted molecular therapies, such as the multikinase inhibitor sorafenib, provide a modest increase in survival for advanced HCC patients and display significant toxicity. Thus, there is an immense need to identify novel regulators of HCC that might be targeted effectively. The insulin-like growth factor (IGF) axis is commonly abnormal in HCC. Upon activation, the IGF axis controls metabolism, tissue homeostasis, and survival. Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein of a family of low-affinity IGF-binding proteins termed "IGFBP-related proteins" that have been identified as a potential tumor suppressor in HCC. IGFBP7 has been implicated in regulating cellular proliferation, senescence, and angiogenesis. In this review, we provide a comprehensive discussion of the role of IGFBP7 in HCC and the potential use of IGFBP7 as a novel biomarker for drug resistance and as an effective therapeutic strategy.

Keywords: HCC; IGFBP7; angiogenesis; apoptosis; gene therapy; senescence.

Figure 1

Insulin-like growth factor-binding protein 7 (IGFBP7) is downregulated in hepatocellular carcinoma (HCC). (A) Tissue microarray using immunohistochemistry examining IGFBP7 expression at/in different stages and grades of HCC. (B) Fluorescent in situ hybridization in normal liver and HCC patient samples showing loss of heterozygosity. Orange, IGFBP7; green, CEP4 (pericentromeric region). Note the loss of one IGFBP7 allele in HCC compared with in normal liver.

Figure 2

Ad.IGFBP7 is an effective therapy for hepatocellular carcinoma (HCC). (A) Bioluminescence imaging of nude mice with established orthotopic tumors in the liver using human HCC cells before (left) and after (right) treatment with Ad.IGFBP7. (B) Photograph of nude mice bearing subcutaneous xenografts from human HCC cells on both flanks treated with control Ad.vec (top) or Ad.IGFBP7 (bottom). Only the left-sided tumors were injected with Ad. Note the almost complete disappearance of both left- and right-sided tumors in Ad.IGFBP7-treated mice. Abbreviation: Rx, treatment.