Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner.
Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner.
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DOI：
10.1016/j.ajur.2015.04.009
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发表时间：
2015-01
影响因子：
2.6
通讯作者：
Rettig MB
中科院分区：
文献类型：
--
作者：
An J;Guo Y;Wang T;Pantuck AJ;Rettig MB
透明细胞肾细胞癌（ccRCC）是肾细胞癌（RCC）最常见的亚型，其特征在于von Hippel-Lindau（VHL）肿瘤抑制基因的双等位基因失活。VHL失活的一个效应是核因子κ B（NF-κB）和c-jun N-末端激酶（JNK）的缺氧诱导因子α（HIFα）非依赖性组成性激活。NF-κB和JNK两者驱动ccRCC生长和上皮向间质转化（EMT）。本研究的目的是确定石榴汁提取物（PE）对肾细胞癌细胞系的生化作用。检测PE对NF-κB、JNK和EMT表型的影响，包括其对pVHL缺陷型RCC的增殖、锚定非依赖性生长和侵袭的影响。PE抑制NF-κB和JNK途径，从而抑制pVHL缺陷型ccRCC的EMT表型。PE的作用是浓度依赖性的，并且不仅影响EMT的生化标志物（即，钙粘蛋白表达），而且还包括EMT的功能性表现，如侵袭。当稀释2000倍时，这些影响在暴露于PE的几天内表现出来。发现高稀释浓度的PE（106稀释度）在短期内不会影响这些途径，但在长期暴露后具有NF-κB和JNK抑制作用和逆转EMT表型的能力。这些研究结果表明，PE可能介导pVHL缺陷型ccRCC的抑制生长，并增加了其作为饮食辅助手段来管理患者的可能性，对小型、局部、偶然发现的肾肿瘤进行积极监测，以避免更具侵入性的手术，例如肾切除术。
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) and is characterized by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. One effect of VHL inactivation is hypoxia inducible factor alpha (HIFα)-independent constitutive activation of nuclear factor kappa B (NF-κB) and c-jun N-terminal kinase (JNK). Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition (EMT). The purpose of this study was to determine the biochemical effects of pomegranate juice extracts (PE) on RCC cell lines. The pre-clinical effects of PE on NF-κB, JNK, and the EMT phenotype were assayed, including its effect on proliferation, anchorage-independent growth, and invasion of pVHL-deficient RCCs. PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs. The effects of PE are concentration-dependent and affect not only biochemical markers of EMT (i.e., cadherin expression) but also functional manifestations of EMT, such as invasion. These effects are manifested within days of exposure to PE when diluted 2000-fold. Highly dilute concentrations of PE (106 dilution), which do not impact these pathways in the short term, were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure. These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small, localized, incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.