White Nicole M A, Newsted Daniel W, Masui Olena, Romaschin Alexander D, Siu K W Michael, Yousef George M
Department of Laboratory Medicine and the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, 30 Bond Street, Toronto, M5B 1W8, Canada.
Tumour Biol. 2014 Mar;35(3):1833-46. doi: 10.1007/s13277-013-1245-6. Epub 2013 Oct 19.
Metastatic renal cell carcinoma (mRCC) is a devastating disease with a 5-year survival rate of approximately 9 % and low response to chemotherapy and radiotherapy. Targeted therapies have slightly improved patient survival, but are only effective in a small subset of patients, who eventually develop resistance. A better understanding of pathways contributing to tumor progression and metastasis will allow for the development of novel targeted therapies and accurate prognostic markers. We performed extensive bioinformatics coupled with experimental validation on proteins dysregulated in mRCC. Gene ontology analysis showed that many proteins are involved in oxidation reduction, metabolic processes, and signal transduction. Pathway analysis showed metabolic pathways are altered in mRCC including glycolysis and pyruvate metabolism, the citric acid cycle, and the pentose phosphate pathway. RT-qPCR analysis showed that genes involved in the citric acid cycle were downregulated in metastatic RCC while genes of the pentose phosphate pathway were overexpressed. Protein-protein interaction analysis showed that most of the 198 proteins altered in mRCC clustered together and many were involved in glycolysis and pyruvate metabolism. We identified 29 reported regions of chromosomal aberrations in metastatic disease that correlate with the direction of protein dysregulation in mRCC. Furthermore, 36 proteins dysregulated in mRCC are predicted to be targets of metastasis-related miRNAs. A more comprehensive understanding of the pathways dysregulated in metastasis can be useful for the development of new therapies and novel prognostic markers. Also, multileveled analyses provide a unique "snapshot" of the molecular "environment" in RCC with prognostic and therapeutic implications.
转移性肾细胞癌（mRCC）是一种极具破坏性的疾病，5年生存率约为9%，对化疗和放疗反应不佳。靶向治疗虽略微提高了患者生存率，但仅对一小部分患者有效，且这些患者最终会产生耐药性。更好地了解促成肿瘤进展和转移的信号通路，将有助于开发新的靶向治疗方法和准确的预后标志物。我们对mRCC中失调的蛋白质进行了广泛的生物信息学分析，并结合实验验证。基因本体分析表明，许多蛋白质参与氧化还原、代谢过程和信号转导。通路分析显示，mRCC中的代谢通路发生改变，包括糖酵解和丙酮酸代谢、柠檬酸循环和磷酸戊糖途径。RT-qPCR分析表明，参与柠檬酸循环的基因在转移性肾细胞癌中下调，而磷酸戊糖途径的基因则过表达。蛋白质-蛋白质相互作用分析表明，mRCC中改变的198种蛋白质中的大多数聚集在一起，许多蛋白质参与糖酵解和丙酮酸代谢。我们在转移性疾病中鉴定出29个报道的染色体畸变区域，这些区域与mRCC中蛋白质失调的方向相关。此外，预测mRCC中失调的36种蛋白质是转移相关miRNA的靶标。对转移过程中失调的信号通路有更全面的了解，可能有助于开发新的治疗方法和新的预后标志物。此外，多层次分析提供了肾细胞癌分子“环境”的独特“快照”，具有预后和治疗意义。
