IGFBP‐4 activates the Wnt/beta‐catenin signaling pathway and induces M‐CAM expression in human renal cell carcinoma

Abstract

The Wnt/b-catenin signaling pathway is inactivated by Wnt antagonists in most cancers and IGFBP-4 is an antagonist of the Wnt/ b-catenin signaling pathway. However, the function of IGFBP-4 is not currently understood in renal cell carcinoma (RCC). We initially found that the expression of IGFBP-4 was significantly lower in primary RCC and higher in metastatic RCC compared to normal human kidney tissues. To assess the function of IGFBP4, we established IGFBP4 transfectants (primary renal cancer cell line) and performed functional analyses including Tcf reporter assays, cell viability, invasive capability, mortality, and in vivo tumor growth. Interestingly IGFBP-4 transfectants promoted cell growth (in vitro and in vivo), invasion, and motility in primary renal cancer. Tcf transcriptional activity was significantly increased in IGFBP-4 transfectants compared to mock cells and b-catenin expression was increased. Also the b-catenin downstream effector, MT1-MMP showed increased expression in IGFBP4 transfectants. Additionally IGFBP4 induced the expression of M-CAM, a marker of tumor progression. In order to assess the role of IGFBP4 in metastatic renal cancer, IGFBP-4 mRNA in a metastatic renal cancer cell lines (ACHN) was knocked-down using a siRNA technique. The cell growth and motility was decreased in si-IGFBP4 transfected ACHN cells compared to cells transfected with control siRNA. Tcf activity in ACHN cells was also decreased with si-IGFBP-4 transfection. This is a first report documenting that IGFBP-4 expression in RCC activates cell growth, metastasis, Wnt/beta-catenin signaling and may be involved in RCC metastasis.

Insulin-like Growth Factor Binding Protein-4 Differentially Inhibits Growth Factor-induced Angiogenesis

“…Similar to these findings, IGFBP-4 exhibited differential inhibitory effects on histologically distinct tumor types as reports have documented the ability of IGFBP-4 to slow the growth of prostate and colon carcinomas, but showed no inhibitory activity in other tumor types such as renal cell carcinoma (23,24,27). Our findings may provide insight to explain in part, the variation in IGFBP-4 inhibitory activity on tumor growth, as angiogenesis within these different tumor types may be driven in part, by distinct growth factor signaling pathways.…”

“…Recently, we showed reduced levels of IGFBP-4 are expressed in human biopsies of metastatic melanoma as compared with primary melanoma (25). However, opposite findings have been documented in other tumor types, reinforcing the complexity of the cell type-and tissue-specific effects of IGFBP-4 (26,27). Interestingly, IGFBP-4 has been shown to modulate the behavior of several distinct cell types, including endothelial and vascular smooth muscle cells, and studies have shown that IGFBP-4 can inhibit endothelial tube formation in vitro, and expression of protease-resistant IGFBP-4 in mammary tumor cells is associated with smaller tumors and fewer blood vessels (28 -32).…”

APC haploinsufficiency coupled with p53 loss sufficiently induces mucinous cystic neoplasms and invasive pancreatic carcinoma in mice

“…Reportedly, IGFBP-4 expression in metastatic renal cell carcinoma is higher than that in primary renal cell carcinoma and normal human kidney tissues. 61 In regard to GCNT4, a glucosaminyl (N-acetyl) transferase 4 core 2, were shown to have a major role in mucin glycan biosynthesis. 62 Additional experiments are required to investigate the precise role of these genes in APC/P53-loss-induced MCNs.…”

Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

“…For example, the expression level of β-catenin has been shown to correlate with progression in colorectal (18), cervical (19), prostate (20), renal cell carcinoma (45,46), hepatocellular carcinoma (47,48), cholangiocarcinoma (26) and several other types of tumors. PGE2 and β-catenin are involved in cholangiocarcinoma progression, and our studies confirm that PGE2 upregulates the β-catenin protein through the EP3-4 receptor.…”