Proteomic changes in renal cancer and co-ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect
Proteomic changes in renal cancer and co-ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect
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DOI：
10.1002/pmic.200300464
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发表时间：
2003-08-01
期刊：
影响因子：
3.4
通讯作者：
Banks, RE
中科院分区：
文献类型：
--
作者：
Unwin, RD;Craven, RA;Banks, RE
肾细胞癌（RCC）是第十大最常见的癌症，虽然发病率正在上升。主要的临床问题源于相对较晚的介绍，许多患者由于往往无症状的性质，疾病和相对不敏感的转移性疾病，以传统的化疗和放疗。尽管越来越多的知识，一些遗传变化的基础散发性肾癌，如涉及冯希佩尔林道（VHL）基因，许多潜在的病理生理变化是不明确的，仍然需要确定的疾病标志物用于诊断和预后或作为潜在的治疗目标。本研究采用蛋白质组学方法，基于二维凝胶电泳和质谱，比较常规RCC组织与患者匹配的正常肾皮质的蛋白质谱。对RCC样本中表达显著增加的32个蛋白质点（大于或等于4/6例患者）和水平降低的41个蛋白质（6/6例患者）进行测序，证实了几种先前已知的RCC相关变化，如Mn-超氧化物歧化酶、乳酸脱氢酶-A、醛缩酶A和C、丙酮酸激酶M2和胸苷磷酸化酶的增加。此外，还发现了一些以前未知的变化，包括膜联蛋白家族三个成员的表达增加和肌动蛋白解聚因子cofilin水平增加。瓦尔堡效应也被证明与糖酵解途径中的大多数步骤中所涉及的蛋白质的鉴定增加和减少的促凝反应，以及在几个线粒体酶的平行减少。通过免疫组织化学、蛋白质印迹和激光捕获显微切割，在其他样本中进一步证实了观察到的一些改变。
Renal cell carcinoma (RCC) is the tenth most common cancer although the incidence is increasing. The main clinical problems stem from the relatively late presentation of many patients due to the often asymptomatic nature of the illness, and the relative insensitivity of metastatic disease to conventional chemotherapy and radiotherapy. Despite increasing knowledge of some of the genetic changes underlying sporadic renal cancer such as those involving the Von Hippel Lindau (VHL) gene, many of the underlying pathophysiological changes are ill-defined and there remains a need for the identification of disease markers for use in diagnosis and prognosis or as potential therapeutic targets. This study has used a proteomic approach, based on two-dimensional gel electrophoresis and mass spectrometry, to compare the protein profiles of conventional RCC tissue with patient-matched normal kidney cortex. Sequencing of 32 protein spots with significantly increased expression in RCC samples (greater than or equal to 4/6 patients) and 41 proteins whose levels decreased (6/6 patients) confirmed several previously known RCC-associated changes such as increases in Mn-superoxide dismutase, lactate dehydrogenase-A, aldolase A and C, pyruvate kinase M2, and thymidine phosphorylase. Additionally, several previously unknown changes were identified, including increased expression of three members of the annexin family and increased levels of the actin depolymerisation factor cofilin. The Warburg effect was also demonstrated with the identification of increases in proteins involved in the majority of steps in the glycolytic pathway and decreases in the gluconeogenic reactions, together with a parallel decrease in several mitochondrial enzymes. A number of the alterations seen were further confirmed in additional samples by immunohistochemistry, Western blotting, and laser capture microdissection.