Underactivation of the adiponectin-adiponectin receptor 1 axis in clear cell renal cell carcinoma: implications for progression
Underactivation of the adiponectin-adiponectin receptor 1 axis in clear cell renal cell carcinoma: implications for progression
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DOI：
10.1007/s10585-013-9618-1
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发表时间：
2014-02-01
影响因子：
4
通讯作者：
Pinthus, Jehonathan H.
中科院分区：
文献类型：
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作者：
Kleinmann, Nir;Duivenvoorden, Wilhelmina C. M.;Pinthus, Jehonathan H.
肾细胞癌（RCC）中通常由5'AMP活化蛋白激酶（AMPK）协调的能量感应途径失调。肥胖可通过其相关的致肥胖激素环境（其特征在于较低的脂联素循环水平）来加重RCC细胞中预先存在的促肿瘤发生代谢机制。在肾细胞癌患者中，低脂联素水平在临床上与更具侵袭性的疾病相关。我们研究了脂联素信号通路在肾细胞癌，重点是脂联素受体1（AdipoR 1）和相关的激活AMPK。采用Western blot和免疫组化方法检测肾癌组织及癌旁正常肾组织中AdipoR 1蛋白的表达。通过VEGF和MMP ELISA以及侵袭实验研究脂联素在体外对RCC细胞的抗肿瘤作用。使用RCC的体内模型，确定AdipoR 1-knockdown（shRNA）对肿瘤潜伏期、生长和扩散的影响。透明细胞肾细胞癌标本中AdipoR 1蛋白显著减少。脂联素处理可抑制肾癌细胞VEGF、MMP-2和MMP-9的分泌和活性，并抑制肾癌细胞的侵袭和迁移能力。AMPK α 1-knockdown（shRNA）减弱脂联素的作用。在稳定表达AdipoR 1特异性shRNA的细胞中，与表达对照shRNA的细胞相比，脂联素对AMPK的激活作用显著降低。在体内，AdipoR 1基因敲低可增加RCC的生长、扩散和血管生成。这些发现表明，整个脂联素激素轴（激素及其受体）的缺陷导致AMPK活化不足，导致RCC血管生成和侵袭能力增加。因此，肥胖和RCC之间的联系可以进一步解释为肥胖个体中的脂联素缺乏以及RCC中的AdipoR 1蛋白减少。
Energy-sensing pathways, normally coordinated by 5' AMP-activated protein kinase (AMPK), are dysregulated in renal cell carcinoma (RCC). Obesity can accentuate the pre-existing pro-tumorigenic metabolic machinery in RCC cells through its associated obesogenic hormonal milieu, characterized by lower circulating levels of adiponectin. In RCC patients, low adiponectin levels associate clinically with more aggressive disease. We investigated the adiponectin signaling pathway in RCC, focusing on adiponectin receptor 1 (AdipoR1) and associated activation of AMPK. AdipoR1 protein in RCC and normal surrounding renal tissues was determined by Western blot analysis and immunohistochemistry. Anti-tumorigenic effects of adiponectin in RCC cells in vitro were investigated via VEGF and MMP ELISA and invasion assays. Using in vivo models of RCC, the effect of AdipoR1-knockdown (shRNA) on tumor latency, growth and dissemination were determined. AdipoR1 protein was significantly reduced in clear cell RCC specimens. Adiponectin treatment inhibited VEGF, MMP-2 and MMP-9 secretion and activity and invasive and migratory capacities of RCC cells. AMPK alpha 1-knockdown (shRNA) attenuated adiponectin's effects. In cells stably expressing AdipoR1-specific shRNA, AMPK activation by adiponectin was significantly reduced compared to cells expressing control shRNA. In vivo, AdipoR1 knockdown increased the growth, dissemination and angiogenesis of RCC. These findings suggest that deficiencies in the entire adiponectin hormonal axis (the hormone and its receptor) result in underactivation of AMPK leading to increased angiogenic and invasive capacities of RCC. The established link between obesity and RCC can therefore be further explained by the adiponectin deficiency in obese individuals together with reduced AdipoR1 protein in RCC.