Insulin-like growth factor binding protein 5 (IGFBP5) functions as a tumor suppressor in human melanoma cells.
Insulin-like growth factor binding protein 5 (IGFBP5) functions as a tumor suppressor in human melanoma cells.
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胰岛素样生长因子结合蛋白 5 (IGFBP5) 在人类黑色素瘤细胞中发挥肿瘤抑制因子的作用
DOI：
10.18632/oncotarget.4114
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发表时间：
2015-08-21
期刊：
影响因子：
--
通讯作者：
Fang X
中科院分区：
文献类型：
--
作者：
Wang J;Ding N;Li Y;Cheng H;Wang D;Yang Q;Deng Y;Yang Y;Li Y;Ruan X;Xie F;Zhao H;Fang X
胰岛素样生长因子结合蛋白5（IGFBP 5）在人类癌症中经常失调，在癌症发生和癌症发展中起着至关重要的作用。然而，IGFBP 5在肿瘤生长和转移中的功能和潜在机制一直是难以捉摸的，特别是在恶性人类黑素瘤中。本研究通过transwell实验、异种移植模型、体内肿瘤转移实验和RNA-Seq等一系列实验，证实IGFBP 5在黑色素瘤的致瘤性和转移中起重要的抑癌作用。IGFBP 5在人黑色素瘤细胞A375中的过表达可显著抑制细胞的恶性行为，包括体外增殖、非贴壁依赖性生长、迁移和侵袭，以及体内肿瘤生长和肺转移。此外，IGFBP 5的过表达抑制上皮-间质转化（EMT），并降低E-钙粘蛋白和关键干细胞标志物NANOG、SOX 2、OCT 4、KLF 4和CD 133的表达。此外，IGFBP 5通过减少IGF 1 R、ERK 1/2和p38-MAPK激酶的磷酸化以及减少HIF 1 α及其靶基因VEGF和MMP 9的表达来发挥其抑制活性。所有这些发现都通过IGFBP 5在人黑素瘤细胞系A2058中的敲低得到证实。总之，这些结果揭示了IGFBP 5作为黑色素瘤进展中的潜在肿瘤抑制剂的机制，表明IGFBP 5可能是人类黑色素瘤的新治疗靶点。
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.