Department of Orthopaedic Surgery, Seoul National University Hospital, 101 Daehak-ro Jongno-gu, Seoul, 03080, South Korea.
Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, South Korea.
BMC Cancer. 2021 Sep 26;21(1):1059. doi: 10.1186/s12885-021-08774-9.
Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell-surface glycoprotein, is overexpressed in several cancer types. EMMPRIN induces a metastatic phenotype by triggering the production of matrix metalloproteinase proteins (MMPs) such as MMP1 and MMP2, and vascular endothelial growth factor (VEGF) in cancer cells and the surrounding stromal cells. The purpose of this study was to investigate the expression and role of EMMPRIN in osteosarcoma.
The level of EMMPRIN expression was evaluated using reverse transcriptase polymerase chain reaction (RT-PCR) in 6 tumor-derived osteosarcoma cell lines and compared with that in normal osteoblasts. To study the prognostic significance of EMMPRIN expression, immunohistochemistry was carried out in prechemotherapy biopsies of 54 patients. siRNA knockdown of EMMPRIN in SaOS-2 cells was conducted to explore the role of EMMPRIN. To study the role of EMMPRIN in tumor-stromal interaction in MMP production and invasion, co-culture of SaOS-2 cells with osteoblasts and fibroblasts was performed. Osteosarcoma 143B cells were injected into the tail vein of BALB/c mice and lung metastasis was analyzed.
EMMRIN mRNA expression was significantly higher in 5 of 6 (83%) tumor-derived cells than in MG63 cells. 90% of specimens (50/54) stained positive for EMMPRIN by immunohistochemistry, and higher expression of EMMPRIN was associated with shorter metastasis-free survival (p = 0.023). Co-culture of SaOS-2 with osteoblasts resulted in increased production of pro-MMP2 and VEGF expression, which was inhibited by EMMPRIN-targeting siRNA. siRNA knockdown of EMMPRIN resulted in decreased invasion. EMMPRIN shRNA-transfected 143B cells showed decreased lung metastasis in vivo.
Our data suggest that EMMPRIN acts as a mediator of osteosarcoma metastasis by regulating MMP and VEGF production in cancer cells as well as stromal cells. EMMPRIN could serve as a therapeutic target in osteosarcoma.
细胞外基质金属蛋白酶诱导因子（EMMPRIN）是一种细胞表面糖蛋白，在多种癌症类型中过度表达。EMMPRIN 通过触发癌细胞和周围基质细胞中基质金属蛋白酶蛋白（MMPs）如 MMP1 和 MMP2 以及血管内皮生长因子（VEGF）的产生，诱导转移表型。本研究旨在探讨 EMMPRIN 在骨肉瘤中的表达和作用。
使用逆转录聚合酶链反应（RT-PCR）评估 6 种肿瘤衍生的骨肉瘤细胞系中 EMMPRIN 的表达水平，并与正常成骨细胞进行比较。为了研究 EMMPRIN 表达的预后意义，对 54 例化疗前活检进行了免疫组织化学分析。通过 siRNA 敲低 SaOS-2 细胞中的 EMMPRIN，探讨 EMMPRIN 的作用。为了研究 EMMPRIN 在 MMP 产生和侵袭中的肿瘤-基质相互作用中的作用，进行了 SaOS-2 细胞与成骨细胞和成纤维细胞的共培养。将骨肉瘤 143B 细胞注射到 BALB/c 小鼠的尾静脉中，分析肺转移情况。
6 种肿瘤衍生细胞中有 5 种（83%）的 EMMPRIN mRNA 表达明显高于 MG63 细胞。90%（50/54）的标本通过免疫组织化学染色呈 EMMPRIN 阳性，较高的 EMMPRIN 表达与无转移生存时间较短相关（p=0.023）。SaOS-2 与成骨细胞共培养导致 pro-MMP2 和 VEGF 表达增加，而 EMMPRIN 靶向 siRNA 抑制了这一过程。siRNA 敲低 EMMPRIN 导致侵袭减少。体内转染 EMMPRIN shRNA 的 143B 细胞显示出肺转移减少。
我们的数据表明，EMMPRIN 通过调节癌细胞和基质细胞中 MMP 和 VEGF 的产生，充当骨肉瘤转移的介质。EMMPRIN 可能成为骨肉瘤的治疗靶点。
