Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma.
Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma.
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DOI：
10.1186/s12967-015-0421-4
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发表时间：
2015-02-12
影响因子：
7.4
通讯作者：
Zhang X
中科院分区：
文献类型：
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作者：
Ma X;Gu L;Li H;Gao Y;Li X;Shen D;Gong H;Li S;Niu S;Zhang Y;Fan Y;Huang Q;Lyu X;Zhang X
虽然肾透明细胞癌（ccRCC）的转移主要在晚期肿瘤中观察到，但ccRCC的早期转移也可以在不确定的分子机制下发现，导致不适当的临床决策和不良预后。斯钙素-1（Stanniocalcin-1，STC 1）是一种糖蛋白激素，参与钙/磷稳态，调节正常发育和肿瘤发生中的各种细胞过程。本研究旨在探讨STC 1在早期ccRCC转移中的作用及其调控机制。通过实时聚合酶链反应（RT-PCR）和蛋白质印迹法测定ccRCC手术标本、RCC细胞系和人肾小管上皮细胞系HKC中STC 1 mRNA和蛋白质表达。免疫组织化学染色（IHC）和免疫荧光法检测STC 1在肾细胞癌组织和癌细胞中的表达和定位。敲低和过表达的研究进行了体外RCC细胞系使用小干扰RNA（siRNA）和慢病毒介导的基因传递，以评估STC 1在细胞增殖，锚定依赖性和独立的生长，细胞周期控制，迁移和侵袭的作用。与非肿瘤组织相比，STC 1 mRNA和蛋白表达在肿瘤中显著上调，在转移组织中观察到的表达增加最大。临床病理分析显示，STC 1 mRNA表达与Fuhrman肿瘤分级（P = 0.008）和总体肿瘤淋巴结转移（TNM）分期（P = 0.018）相关。与局限性肿瘤相比，STC 1在T1期转移性肿瘤中的表达升高，并且与平均肿瘤直径呈正相关。通过Caki-1和A498沉默STC 1的表达导致细胞增殖、迁移和侵袭的抑制，同时STC 1的下调损害ccRCC细胞系的上皮-间质转化（EMT）。在Caki-2中过表达STC 1可促进细胞生长和增殖，但不能促进细胞迁移和侵袭。进一步的研究表明缺氧和HIF-1α是STC 1表达的候选调节因子。我们的研究结果证明了STC 1在早期ccRCC转移中的作用，并表明STC 1可能是这种疾病预后和指导手术策略和辅助治疗临床决策的潜在价值的生物标志物。本文的在线版本（doi：10.1186/s12967-015-0421-4）包含补充材料，可供授权用户使用。
Although metastasis of clear cell renal cell carcinoma (ccRCC) is predominantly observed in late stage tumors, early stage metastasis of ccRCC can also be found with indefinite molecular mechanism, leading to inappropriate clinical decisions and poor prognosis. Stanniocalcin-1 (STC1) is a glycoprotein hormone involved in calcium/phosphate homeostasis, which regulates various cellular processes in normal development and tumorigenesis. This study aimed to investigate the role and mechanism of regulation of STC1 in the metastasis of early stage ccRCC. STC1 mRNA and protein expression was determined in ccRCC surgical specimens, RCC cell lines, and human kidney tubule epithelial cell line HKC by real-time polymerase chain reaction (RT-PCR) and western blotting. Immunohistochemistry staining (IHC) and immunofluorescence were also used to examine the expression and localization of STC1 in ccRCC tissues and cancer cells. Knockdown and overexpression studies were conducted in vitro in RCC cell lines using small interfering RNAs (siRNA) and lentiviral-mediated gene delivery to evaluate the role of STC1 in cell proliferation, anchorage-dependent and independent growth, cell cycle control, and migration and invasion. STC1 mRNA and protein expression were significantly up-regulated in tumors when compared with non-tumor tissues, with the greatest increase in expression observed in metastatic tissues. Clinicopathological analysis revealed that STC1 mRNA expression was associated with Fuhrman tumor grade (P = 0.008) and overall Tumor Node Metastasis (TNM) staging (P = 0.018). STC1 expression was elevated in T1 stage metastatic tumors when compared with localized tumors, and was positively correlated with average tumor diameter. Silencing of STC1 expression by Caki-1 and A498 resulted in the inhibition of cell proliferation, migration, and invasion, meanwhile down-regulation of STC1 impaired epithelial–mesenchymal transition (EMT) of ccRCC cell lines. Overexpression of STC1 in Caki-2 enhanced cell growth and proliferation but not migration and invasion. Further investigation identified hypoxia and HIF-1α as candidate regulators of STC1 expression. Our findings demonstrate a role for STC1 in metastasis of early stage ccRCC and suggest that STC1 may be a biomarker of potential value both for the prognosis of this disease and for guiding clinical decisions regarding surgical strategies and adjuvant treatment. The online version of this article (doi:10.1186/s12967-015-0421-4) contains supplementary material, which is available to authorized users.
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影响因子：
1.8
作者：
Kikuchi, Masato;Nakano, Yasuko;Imakawa, Kazuhiko
通讯作者：
Imakawa, Kazuhiko
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影响因子：
11
作者：
He LF;Wang TT;Gao QY;Zhao GF;Huang YH;Yu LK;Hou YY
通讯作者：
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影响因子：
4.1
作者：
McCudden, CR;Majewski, A;Wagner, GF
通讯作者：
Wagner, GF
影响因子：
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作者：
Jung M;Ramankulov A;Roigas J;Johannsen M;Ringsdorf M;Kristiansen G;Jung K
通讯作者：
Jung K
影响因子：
19.6
作者：
通讯作者：
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