Skp2 regulates subcellular localization of PPARγ by MEK signaling pathways in human breast cancer.
Skp2 regulates subcellular localization of PPARγ by MEK signaling pathways in human breast cancer.
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DOI：
10.3390/ijms140816554
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发表时间：
2013-08-09
影响因子：
5.6
通讯作者：
Dai S
中科院分区：
文献类型：
--
作者：
Cheng H;Meng J;Wang G;Meng Y;Li Y;Wei D;Fu C;Deng K;Shen A;Wang H;Dai S
核激素受体家族成员PPARγ在乳腺肿瘤发生中起重要作用。已有研究表明，PPARγ在TPA刺激下具有胞质活性。然而，细胞质PPARγ在人类乳腺癌中的临床病理意义尚不完全清楚。Skp2具有致癌性，其频繁扩增和过表达与恶性肿瘤的分级相关。在这项研究中，研究了细胞质PPARγ和Skp2表达在人类乳腺癌进展中的作用。因此，对70例标本经福尔马林固定的石蜡切片进行免疫组织化学分析。利用Western blot和免疫荧光显微镜分析体外培养的人乳腺癌细胞细胞质中PPARγ和Skp2表达的关系。结果显示，细胞质PPARγ表达与Skp2表达呈正相关（p < 0.05），与雌激素受体表达（p = 0.026）、病理分级（p = 0.029）显著相关。此外，通过核细胞质分离技术和免疫荧光显微镜分析，Skp2过表达可以通过mek1依赖机制在人乳腺癌细胞中引起PPARγ的细胞质定位。利用RNA干扰技术，我们还发现Skp2的下调降低了MEK1的磷酸化水平，并显著逆转了tpa诱导的MDA-MB-231细胞中PPARγ的核输出。PPARγ亚细胞定位的变化可能代表了乳腺癌患者选择性干扰的新靶点。
Nuclear hormone receptor family member PPARγ plays an important role in mammary gland tumorigenesis. Previous studies have shown PPARγ has cytoplasmic activities upon tetradecanoyl phorbol acetate (TPA) stimulation. However, the clinical pathological significance of cytoplasmic PPARγ is not completely understood in human breast cancer. Skp2 is oncogenic, and its frequent amplification and overexpression correlated with the grade of malignancy. In this study, the role of cytoplasmic PPARγ and Skp2 expression was investigated in human breast cancer progression. Therefore, immunohistochemical analysis was performed on formalin-fixed paraffin sections of 70 specimens. Furthermore, Western blot and immunofluorescence microscopy analysis were used to study the relationship between expression of cytoplasmic PPARγ and Skp2 expression in human breast cancer cells in vitro. Results showed that the expression of cytoplasmic PPARγ was positively correlated with Skp2 expression (p < 0.05), and correlated significantly with estrogen receptor (p = 0.026) and pathological grade (p = 0.029), respectively. In addition, Skp2 overexpression can provoke cytoplasmic localization of PPARγ upon MEK1-dependent mechanisms in human breast cancer cells by nuclear-cytosolic fractionation technology and immunofluorescence microscopy analysis. Using RNA interference technology, we also found that down-regulated Skp2 reduced the phosphorylation level of MEK1 and significantly reversed TPA-induced nuclear export of PPARγ in MDA-MB-231 cells. The changes in the subcellular localization of PPARγ may represent a novel target for selective interference in patients with breast cancer.
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影响因子：
4.8
作者：
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