Li Xiangyu, Turanli Beste, Juszczak Kajetan, Kim Woonghee, Arif Muhammad, Sato Yusuke, Ogawa Seishi, Turkez Hasan, Nielsen Jens, Boren Jan, Uhlen Mathias, Zhang Cheng, Mardinoglu Adil
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
Department of Bioengineering, Istanbul Medeniyet University, Istanbul, Turkey.
Heliyon. 2020 Feb 19;6(2):e03440. doi: 10.1016/j.heliyon.2020.e03440. eCollection 2020 Feb.
Clear cell renal cell carcinoma (ccRCC) accounts for 70-80% of kidney cancer diagnoses and displays high molecular and histologic heterogeneity. Hence, it is necessary to reveal the underlying molecular mechanisms involved in progression of ccRCC to better stratify the patients and design effective treatment strategies. Here, we analyzed the survival outcome of ccRCC patients as a consequence of the differential expression of four transcript isoforms of the pyruvate kinase muscle type (). We first extracted a classification biomarker consisting of eight gene pairs whose within-sample relative expression orderings (REOs) could be used to robustly classify the patients into two groups with distinct molecular characteristics and survival outcomes. Next, we validated our findings in a validation cohort and an independent Japanese ccRCC cohort. We finally performed drug repositioning analysis based on transcriptomic expression profiles of drug-perturbed cancer cell lines and proposed that paracetamol, nizatidine, dimethadione and conessine can be repurposed to treat the patients in one of the subtype of ccRCC whereas chenodeoxycholic acid, fenoterol and hexylcaine can be repurposed to treat the patients in the other subtype.
透明细胞肾细胞癌（ccRCC）占肾癌诊断病例的70 - 80%，并表现出高度的分子和组织学异质性。因此，有必要揭示ccRCC进展过程中潜在的分子机制，以便更好地对患者进行分层并设计有效的治疗策略。在此，我们分析了丙酮酸激酶肌肉型（）四种转录本异构体的差异表达对ccRCC患者生存结果的影响。我们首先提取了一个由八个基因对组成的分类生物标志物，其样本内相对表达顺序（REO）可用于将患者稳健地分为两组，这两组具有不同的分子特征和生存结果。接下来，我们在一个验证队列和一个独立的日本ccRCC队列中验证了我们的发现。我们最后基于药物扰动癌细胞系的转录组表达谱进行了药物重新定位分析，并提出对乙酰氨基酚、尼扎替丁、二甲双酮和锥丝碱可重新用于治疗ccRCC一种亚型的患者，而鹅去氧胆酸、非诺特罗和辛可卡因可重新用于治疗另一种亚型的患者。
