Heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1) was purified from A431 cell-conditioned media based on its capacity to bind to fibroblast growth factor 1 and 2 (FGF-1 and FGF-2). HBp17/FGFBP-1 has been observed to induce the tumorigenic potential of epithelial cells and is highly expressed in oral cancer cell lines and tissues. HBp17/FGFBP-1 is also recognized as a pro-angiogenic molecule as a consequence of its interaction with FGF-2. We have previously reported that Eldecalcitol (ED-71), an analog of 1α,25(OH)2D3, downregulated the expression of HBp17/FGFBP-1 and inhibited the proliferation of squamous cell carcinoma (SCC) cells in vitro and in vivo through NF-κb inhibition. To explore the possibility of microRNA (miRNA) control of HBp17/FGFBP-1, we analyzed exosomal miRNAs from medium conditioned by A431 cells treated with ED-71. Microarray analysis revealed that 12 exosomal miRNAs were upregulated in ED-71-treated A431 cells. Among them, miR-6887-5p was identified to have a predicted mRNA target matching the 3' untranslated region (3'-UTR) of HBp17/FGFBP-1. The 3'-UTR of HBp17/FGFBP-1 was confirmed to be a direct target of miR-6887-5p in SCC/OSCC cells, as assessed with a luciferase reporter assay. Functional assessment revealed that overexpression of miR-6887-5p in SCC/OSCC cells inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in vivo compared with control. In conclusion, our present study supports a novel anti-cancer mechanism involving the regulation of HBp17/FGFBP-1 function by exosomal miR-6887-5p in SCC/OSCC cells, which has potential utility as a miRNA-based cancer therapy.

中文翻译：

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去甲骨化醇（ED-71）诱导的外泌体miR-6887-5p通过靶向肝素结合蛋白17 /成纤维细胞生长因子结合蛋白-1（HBp17 / FGFBP-1）抑制鳞状细胞癌细胞的生长。

从肝素结合蛋白17 /成纤维细胞生长因子结合蛋白1（HBp17 / FGFBP-1）中纯化出肝素结合蛋白17 /成纤维细胞生长因子结合蛋白-1（HBp17 / FGFBP-1），基于其结合成纤维细胞生长因子1和2（FGF-1和FGF-2）的能力）。已观察到HBp17 / FGFBP-1诱导上皮细胞的致瘤潜力，并在口腔癌细胞系和组织中高表达。由于HBp17 / FGFBP-1与FGF-2相互作用，因此也被认为是促血管生成分子。我们以前曾报道过Eldecalcitol（ED-71）（1α，25（OH）2D3的类似物）在体外和体内下调HBp17 / FGFBP-1的表达并抑制鳞状细胞癌（SCC）细胞的增殖。 NF-κb抑制。为了探讨HBp17 / FGFBP-1的microRNA（miRNA）控制的可能性，我们分析了以ED-71处理的A431细胞为条件的培养基中的外泌体miRNA。基因芯片分析显示，经ED-71处理的A431细胞中有12种外泌体miRNA上调。其中，已确定miR-6887-5p具有与HBp17 / FGFBP-1的3'非翻译区（3'-UTR）匹配的预测的mRNA靶标。如萤光素酶报告基因分析所评估，证实HBp17 / FGFBP-1的3'-UTR是SCC / OSCC细胞中miR-6887-5p的直接靶标。功能评估表明，与对照组相比，miR-6887-5p在SCC / OSCC细胞中的过量表达在体外抑制细胞增殖和集落形成，并在体内抑制肿瘤生长。总而言之，我们的研究支持一种新型的抗癌机制，涉及通过外泌体miR-6887-5p在SCC / OSCC细胞中调节HBp17 / FGFBP-1功能，