IGFBP7: an oncosuppressor gene in thyroid carcinogenesis

Abstract

Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein involved in several cellular processes, including proliferation, senescence and apoptosis. Loss of IGFBP7 expression is a critical step in the development of human tumors, including melanoma and colon cancer. By microarray gene expression studies, we have detected downregulation of IGFBP7 gene expression in follicular and papillary thyroid tumors in comparison with normal thyroid tissue. Evaluation of publicly available PTC microarray gene expression data sets confirmed, in a consistent fraction of tumors, the downregulation of IGFBP7 transcript levels. The functional consequence of IGFBP7 downregulation was addressed in the PTCderived NIM1 cell line in which IGFBP7 expression is repressed by promoter hypermethylation. Exposure to soluble IGFBP7 protein or restoration of IGFBP7 expression by complementary DNA transfection reduced growth rate, migration, anchorage-independent growth and tumorigenicity of NIM1 cells. We show that the effects of IGFBP7 are related to apoptosis. Our data suggest that loss of IGFBP7 expression has a functional role in thyroid carcinogenesis, and it may represent a possible basis for therapeutic strategies.

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

“…Although a role for tumor-suppressor genes in thyroid carcinogenesis has not been assessed yet, functional studies have allowed some genes downregulated in PTCs to be classified as tumor suppressors, based on their ability to modulate transformed properties of thyroid tumor cell lines (Ferrario et al, 2008;Latini et al, 2008;Pallante et al, 2008;Vizioli et al, 2010;Zuo et al, 2010). With this study, we have demonstrated that TIMP3 exerts a negative regulatory role in thyroid tumor cells, thus corroborating its oncosuppressor role suggested by hypermetylation and gene expression studies.…”

“…In addition to the BRAFV600E mutation, NIM1 cells carry homozygous deletion of the tumor-suppressor p16INK4 (Calabro et al, 1996), produce multiple cytokines, including GM-CSF, IL-6 and IL-11, and their growth is regulated by IL-1 through an autocrine mechanism (Tohyama et al, 1992;Zeki et al, 1993). Moreover, we have recently demonstrated that the growth of NIM1 cells is regulated by an autocrine transforming growth factor-a/epidermal growth factor receptor loop (Degl'Innocenti et al, 2010) and by the IGFBP7 pathway (Vizioli et al, 2010).…”

“…Soft agar assay Soft agar assay was performed as previously described (Vizioli et al, 2010). Pictures were taken at  4 magnification using a digital camera system coupled with a microscope (LEICA, DMIRB).…”

“…Putative oncosuppressor genes relevant for thyroid carcinomas have been suggested by methylation studies (Xing 2007(Xing , 2008. In the past few years, some genes identified as downregulated in the context of gene expression studies were classified as tumor suppressors by functional studies, as their re-expression modulated transformed properties of thyroid carcinoma cell lines (Ferrario et al, 2008;Latini et al, 2008;Pallante et al, 2008;Vizioli et al, 2010;Zuo et al, 2010).…”

Breakpoint determination of X;autosome balanced translocations in four patients with premature ovarian failure

“…Recently, it is reported that IGFBP7 loss has a functional role in thyroid carcinogenesis. 20 C14orf159 is a hypothetical protein with unknown function. Both disrupted genes were relatively expressed in ovary based on the GeneCards database (http://www.…”