Abstract
The insulin-like growth factor binding protein 5 (IGFBP5), which is often dysregulated in human cancers, plays a crucial role in carcinogenesis and cancer development. However, the function and underlying mechanism of IGFBP5 in tumor growth and metastasis has been elusive, particularly in malignant human melanoma. Here, we reported that IGFBP5 acts as an important tumor suppressor in melanoma tumorigenicity and metastasis by a series of experiments including transwell assay, xenograft model, in vivo tumor metastasis experiment, and RNA-Seq. Overexpression of IGFBP5 in A375, a typical human melanoma cell line, inhibited cell malignant behaviors significantly, including in vitro proliferation, anchorage-independent growth, migration and invasion, as well as in vivo tumor growth and pulmonary metastasis. In addition, overexpression of IGFBP5 suppressed epithelial-mesenchymal transition (EMT), and decreased the expression of E-cadherin and the key stem cell markers NANOG, SOX2, OCT4, KLF4, and CD133. Furthermore, IGFBP5 exerts its inhibitory activities by reducing the phosphorylation of IGF1R, ERK1/2, and p38-MAPK kinases and abating the expression of HIF1α and its target genes, VEGF and MMP9. All these findings were confirmed by IGFBP5 knockdown in human melanoma cell line A2058. Taken together, these results shed light on the mechanism of IGFBP5 as a potential tumor-suppressor in melanoma progression, indicating that IGFBP5 might be a novel therapeutic target for human melanoma.
Highlights
The insulin-like growth factor binding proteins (IGFBPs) comprise a family of six proteins that function as critical regulators of the bioavailability and mitogenic activities of insulin-like growth factors (IGFs)
insulin-like growth factor binding protein 5 (IGFBP5) has been associated with various types of cancers, acting in oncogenic or tumor-suppressive roles, such as breast cancer [4, 6, 14,15,16], osteosarcoma [5, 17, 18], head and neck squamous cell carcinoma [19], neuroblastoma [20], or prostate cancer [21], little is known about the role of IGFBP5 in human MM
It is widely accepted that MM is driven by the activation of MEK-extracellular signalregulated kinase (ERK) signaling pathway, typically through mutations in the BRAF or NRAS oncogenes, as well as upstream membrane receptors (e.g. EGFR and IGF 1 receptor www.impactjournals.com/oncotarget (IGF1R)) [27,28,29,30,31,32]. p38-MAPKs play a vital role in the progression of melanoma [33, 34]
Summary
The insulin-like growth factor binding proteins (IGFBPs) comprise a family of six proteins that function as critical regulators of the bioavailability and mitogenic activities of insulin-like growth factors (IGFs). IGFBP5, the most conserved member of the IGFBPs family, is frequently dysregulated in human cancers and metastatic tissues [1, 2]. IGFBP5 has several functional roles in carcinogenesis and cancer development, which can determine cell survival and regulate cell growth, migration, and invasion in the development of cancer. Many preclinical studies indicate that IGFBP5 can suppress tumor growth and metastasis in various tissues and contexts, but IGFBP5 can function as an oncogene, promoting metastasis in a context-dependent manner [2,3,4]. The different domains of IGFBP5 exert distinct effects on the tumorigenicity and metastasis of different human cancers [5, 6]
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