Department of Otolaryngology, Xiangya Hospital, Central South University, Xiangya Road, Changsha, Hunan, China.
Arch Med Res. 2011 Feb;42(2):128-37. doi: 10.1016/j.arcmed.2011.03.003.
Bone morphogenetic proteins (BMPs) have recently been shown to be involved in the genesis and progression of a wide variety of carcinomas. The present study was undertaken to estimate the effect of BMP-4 on squamous cell carcinoma of the head and neck (SCCHN) in tissue and cell levels.
In this study, immunohistochemistry, Western blotting and RT-PCR were utilized to detect the expression of BMP-4, Smad1 and phosphorylated Smad1 in SCCHN tissues or SCCHN cell lines. Those three proteins in tissues were further correlated with prognosis of SCCHN by Kaplan-Meier analysis. The epithelial-mesenchymal transition (EMT)-associated changes in SCCHN cells were detected after stimulation by human BMP-4 recombinant protein and knockdown of Smad1 gene. Meanwhile, the effect on invasiveness and migration was evaluated by invasion and scratch assays, respectively.
BMP-4 and p-Smad1 protein were overexpressed in SCCHN tissues with cervical lymph node metastasis, which was significantly higher than those without metastasis. The expression of BMP-4 and p-Smad1 protein was negatively correlated with the prognosis of SCCHN. BMP-4 promoted the invasiveness and migration through EMT, which was demonstrated by morphological alterations, loss of E-cadherin, increase of vimentin and activation of the Smad1 signal pathway. Knockdown of Smad1 expression suppressed BMP-4 induced EMT in both cell lines and weakened the invasiveness and migration of Tu686 and Tu212 in vitro.
Our results demonstrate that BMP-4 protein may contribute to the malignant metastasis of SCCHN, which presents as a novel prognostic marker and a potential therapeutic target for patients with SCCHN.
骨形态发生蛋白（BMPs）最近被证明参与了多种癌的发生和发展。本研究旨在评估 BMP-4 对头颈部鳞状细胞癌（SCCHN）在组织和细胞水平上的影响。
在这项研究中，我们利用免疫组织化学、Western blot 和 RT-PCR 检测了 BMP-4、Smad1 和磷酸化 Smad1 在 SCCHN 组织或 SCCHN 细胞系中的表达。通过 Kaplan-Meier 分析，进一步将这三种蛋白与 SCCHN 的预后进行相关性分析。在人 BMP-4 重组蛋白刺激和 Smad1 基因敲低后，检测 SCCHN 细胞中上皮-间充质转化（EMT）相关的变化。同时，通过侵袭和划痕实验分别评估对侵袭和迁移的影响。
BMP-4 和 p-Smad1 蛋白在伴有颈部淋巴结转移的 SCCHN 组织中过表达，明显高于无转移者。BMP-4 和 p-Smad1 蛋白的表达与 SCCHN 的预后呈负相关。BMP-4 通过 EMT 促进侵袭和迁移，这表现在形态改变、E-钙黏蛋白丢失、波形蛋白增加和 Smad1 信号通路激活。Smad1 表达的敲低抑制了两种细胞系中 BMP-4 诱导的 EMT，并减弱了 Tu686 和 Tu212 在体外的侵袭和迁移。
我们的结果表明，BMP-4 蛋白可能有助于 SCCHN 的恶性转移，可作为一种新的预后标志物和 SCCHN 患者的潜在治疗靶点。
