Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis
Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis
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DOI：
10.1038/sj.onc.1207555
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发表时间：
2004-05-13
期刊：
影响因子：
8
通讯作者：
Toyokuni, S
中科院分区：
文献类型：
--
作者：
Tanaka, T;Akatsuka, S;Toyokuni, S
次氮基三乙酸铁（Fe-NTA）可诱导大鼠肾氧化损伤，导致肾细胞癌（RCC）的高发病率。这种RCC的差异显示分析显示膜联蛋白2（Anx 2），激酶的底物和组织型纤溶酶原激活剂和纤溶酶原的受体的表达升高。我们进行了这项研究，以阐明Anx 2在芬顿反应为基础的致癌作用的意义。在Fe-NTA给药后的大鼠肾脏中以及暴露于H2 O2后的LLC-PK 1细胞中，Anx 2的mRNA和蛋白水平呈时间依赖性增加。后者被抑制预处理N-乙酰半胱氨酸，吡咯烷二硫代氨基甲酸酯或过氧化氢酶。免疫组化显示正常肾近端小管染色可忽略不计，但在再生近端小管、巨核细胞和RCC中染色强烈。转移性RCC显示较高的Anx 2蛋白水平。Anx 2在这些细胞中的丝氨酸和酪氨酸残基磷酸化，并与磷酸化肌动蛋白共免疫沉淀。过表达Anx 2可诱导LLC-PK 1细胞增殖。与此相反，在Anx 2反义处理后，观察到从Fe-NTA诱导的RCC建立的细胞系的增殖减少，导致细胞凋亡。这些结果表明，Anx 2是由氧化还原状态调节，这种适应性机制的持续运作在氧化应激诱导的癌症的增殖和转移中发挥作用。
Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal damage leading to a high incidence of renal cell carcinoma (RCC) in rats. Differential display analysis of such RCCs revealed elevated expression of annexin 2 (Anx2), a substrate for kinases and a receptor for tissue-type plasminogen activator and plasminogen. We conducted this study to clarify the significance of Anx2 in Fenton reaction-based carcinogenesis. Messenger RNA and protein levels of Anx2 were increased time-dependently in the rat kidney after Fe-NTA administration as well as in LLC-PK1 cells after exposure to H2O2. The latter was inhibited by pretreatment with N-acetylcysteine, pyrrolidine dithiocarbamate or catalase. Immunohistochemistry revealed negligible staining in the normal renal proximal tubules, but strong staining in regenerating proximal tubules, karyomegalic cells and RCCs. Metastasizing RCCs showed higher Anx2 protein levels. Anx2 was phosphorylated at serine and tyrosine residues in these cells and coimmunoprecipitated with phosphorylated actin. Overexpression of Anx2 induced a higher cell proliferation rate in LLC-PK1 cells. In contrast, a decrease in proliferation leading to apoptosis was observed after Anx2 antisense treatment to cell lines established from Fe-NTA-induced RCCs. These results suggest that Anx2 is regulated by redox status, and that persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer.