PI3K/AKT/mTOR pathway plays a major pathogenetic role in glycogen accumulation and tumor development in renal distal tubules of rats and men.
PI3K/AKT/mTOR pathway plays a major pathogenetic role in glycogen accumulation and tumor development in renal distal tubules of rats and men.
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DOI：
10.18632/oncotarget.3675
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发表时间：
2015-05-30
期刊：
影响因子：
--
通讯作者：
Dombrowski F
中科院分区：
文献类型：
--
作者：
Ribback S;Cigliano A;Kroeger N;Pilo MG;Terracciano L;Burchardt M;Bannasch P;Calvisi DF;Dombrowski F
PI3K/AKT/mTOR通路的激活在人透明细胞肾细胞癌（ccRCC）中是一个重要的分子事件，在糖尿病肾病中也是上调的。糖尿病大鼠的代谢变化影响肾远端小管上皮，导致糖原储存的Armanni-Ebstein病变（AEL），这是糖尿病肾病模型中RCC的前体病变。这些病变类似于人类散发性透明细胞小管（CCT）和人类ccRCC的肿瘤细胞。在324例肾切除标本中检测了人类散发性CCT的形态学、代谢和分子变化，并将其与链脲佐菌素诱导的糖尿病或n-亚硝基卟啉引起的大鼠肿瘤前CCT和RCC进行了比较。糖尿病大鼠和非糖尿病大鼠分别给予双PI3K/mTOR抑制剂NVP/BEZ235。17.3%的肾脏标本检出人散发CCT。人和大鼠肾CCT强烈诱导PI3K/AKT/mTOR通路及相关代谢改变。参与糖酵解和新生脂肪生成的蛋白质上调。在体内实验中，PI3K和mTOR的双重抑制导致大鼠糖尿病相关CCT的增殖减少，自噬活性增加。目前的数据表明，人类散发性CCT在大鼠模型中表现出与肿瘤前病变相似的形态和代谢改变模式。糖原小管中PI3K/AKT/mTOR通路的激活是一个显著的分子事件，表明这些病变在人类中也具有肿瘤前特征。
Activation of the PI3K/AKT/mTOR pathway is a crucial molecular event in human clear cell renal cell carcinoma (ccRCC), and is also upregulated in diabetic nephropathy. In diabetic rats metabolic changes affect the renal distal tubular epithelium and lead to glycogen-storing Armanni-Ebstein lesions (AEL), precursor lesions of RCC in the diabetes induced nephrocarcinogenesis model. These lesions resemble human sporadic clear cell tubules (CCT) and tumor cells of human ccRCC. Human sporadic CCT were examined in a collection of 324 nephrectomy specimen, in terms of morphologic, metabolic and molecular alterations, and compared to preneoplastic CCT and RCC developed in the rat following streptozotocin-induced diabetes or N-Nitrosomorpholine administration. Diabetic and non-diabetic rats were subjected to the dual PI3K/mTOR inhibitor, NVP/BEZ235. Human sporadic CCT could be detected in 17.3% of kidney specimens. Human and rat renal CCT display a strong induction of the PI3K/AKT/mTOR pathway and related metabolic alterations. Proteins involved in glycolysis and de novo lipogenesis were upregulated. In in vivo experiments, dual inhibition of PI3K and mTOR resulted in a reduction of proliferation of rat diabetes related CCT and increased autophagic activity. The present data indicate that human sporadic CCT exhibit a pattern of morphologic and metabolic alterations similar to preneoplastic lesions in the rat model. Activation of the PI3K/AKT/mTOR pathway in glycogenotic tubuli is a remarkable molecular event and suggests a preneoplastic character of these lesions also in humans.