Biology of insulin-like growth factor binding protein-4 and its role in cancer (review)

Durai, Rajaraman; Davies, Mark; Yang, Wenxuan; Yang, Shi Yu; Seifalian, Alexander M.; Goldspink, G.; Winslet, Marc C.

doi:10.3892/ijo.28.6.1317

Cited by 62 publications

(82 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The identification of IGFBP-4 as an inhibitor of Wnt/b-catenin signalling may also have some implications for cancer biology 16 . It was shown that treatment with IGFBP-4 reduces cell proliferation in some cancer cell lines in vitro, and that overexpression of IGFBP-4 attenuates the growth of prostate cancer in vivo.…”

mentioning

confidence: 99%

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Zhu

Shiojima

Ito

et al. 2008

Nature

207

165

View full text Add to dashboard Cite

Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs) 1 . Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown 1,2 . Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, lowdensity lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.The heart is the first organ to form during embryogenesis, and abnormalities in this process result in congenital heart diseases, the most common cause of birth defects in humans 3 . Molecules that mediate cardiogenesis are of particular interest because of their potential use for cardiac regeneration 4,5 . Previous studies have shown that soluble growth factors such as bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), Wnts and Wnt inhibitors mediate the tissue interactions that are crucial for cardiomyocyte specification 3,4 . We proposed that there might be additional soluble factors that modulate cardiac development and/or cardiomyocyte differentiation.P19CL6 cells differentiate into cardiomyocytes with high efficiency in the presence of 1% dimethylsulphoxide (DMSO) 6 . We cultured P19CL6 cells with culture media conditioned by various cell types in the absence of DMSO, and screened the cardiogenic activity of the conditioned media. The extent of cardiomyocyte differentiation was assessed by the immunostaining with MF20 monoclonal antibody that recognizes sarcomeric myosin heavy chain (MHC). Among the several cell types tested, culture media conditioned by a murine stromal cell line OP9 induced cardiomyocyte differentiation of P19CL6 cells without DMSO treatment (Fig. 1a, left and middle panels). Increased MF20-positive area was accompanied by the induction of cardiac marker genes such as aMHC, Nkx2.5 and GATA-4, and by the increased protein levels of cardiac troponin T (cTnT) (Fig. 1a, right panel). In contrast, culture media conditioned by COS7 cells, mouse embryonic fibroblasts, NIH3T3 cells, HeLa cells, END2 cells (visceral endoderm-like cells), neonatal rat cardiomyocytes and neonatal rat cardiac fibroblasts did not induce cardiomyocyte differentiation of P19CL6 cells in the absence of DMSO (Fig. 1a and data not shown). From these observations, we p...

show abstract

mentioning

confidence: 99%

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Zhu

Shiojima

Ito

et al. 2008

Nature

207

165

View full text Add to dashboard Cite

show abstract

“…It was reported in inhibiting colon cancer growth (7,15 (9). Salinomycin has been evaluated by several studies in various types of cancer stem cells (16)(17)(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

IGFBP‑4 expression is adversely associated with lung cancer prognosis

et al. 2017

View full text Add to dashboard Cite

Abstract. Insulin-like growth factor binding protein-4 (IGFBP-4) was reported to be associated with prognosis in several types of cancer; however, to the best of our knowledge, whether it is correlated with lung cancer has yet to be reported. In the present study, 102 pairs of lung cancer tissues and surrounding non-cancerous tissues (SNCTs) were collected. The IGFBP-4 levels in tissues were detected with immunohistochemistry. The relevance of IGFBP-4 to the survival of patients was assessed. The IGFBP-4 gene was knocked down, and its function in the proliferation of lung cancer cells was measured. The percentage of lung cancer tissues with higher IGFBP-4 expression than SNCTs (51.9%) was increased compared with the percentage with similar (11.76%) or lower (36.27%) IGFBP-4 expression. Patients with higher IGFBP-1 expression exhibited a shorter median survival time. IGFBP-1 was associated with metastasis, lung cancer stages and malignancy, but not with age, sex or tumor size. Lung cancer cells with stably knocked down IGFBP-4 showed an inhibitory proliferation rate. The present study identified that IGFBP-4 was adversely associated with the prognosis of lung cancer patients. IGFBP-4 knockdown prohibited lung cancer cell growth. The present study provides a potential marker for lung cancer diagnosis and a possible target for lung cancer therapy.

show abstract

“…Treatment with IGFBP-4 reduces cell proliferation in some cancer cell lines in vitro, and overexpression of IGFBP-4 attenuates the growth of prostate cancer in vivo (Durai et al 2006).…”

Section: Igfbp-4mentioning

confidence: 99%