de Carvalho Paulo Afonso, Bonatelli Murilo, Cordeiro Maurício Dener, Coelho Rafael Ferreira, Reis Sabrina, Srougi Miguel, Nahas Willian Carlos, Pinheiro Celine, Leite Katia Ramos Moreira
Faculdade de Medicina da Universidade de Sao Paulo, Laboratory of Medical Investigation (LIM55)-Urology Department, Sao Paulo, Brazil.
Instituto do Câncer do Estado de Sao Paulo (ICESP), Sao Paulo, Brazil.
Carcinogenesis. 2021 Dec 31;42(12):1420-1427. doi: 10.1093/carcin/bgab100.
Clear cell renal cell carcinoma (ccRCC) has been considered a metabolic disease, with loss of von Hippel-Lindau (VHL) gene and consequent overexpression of hypoxia-inducible factor 1 alpha (HIF-1α), which is central for tumor development and progression. Among other effects, HIF-1α is involved in the metabolic reprogramming of cancer cells towards the Warburg effect involved in tumor cell proliferation, migration and survival. In this context, several proteins are expressed by cancer cells, including glucose and lactate transporters as well as different pH regulators. Among them, monocarboxylate transporters (MCTs) can be highlighted. Our aim is to comprehensively analyze the immunoexpression of MCT1, MCT2, MCT4, CD147, CD44, HIF-1α, GLUT1 and CAIX in ccRCC surgical specimens correlating with classical prognostic factors and survival of patients with long follow-up. Surgical specimens from 207 patients with ccRCC who underwent radical or partial nephrectomy were used to build a tissue microarray. Immunostaining was categorized into absent/weak or moderate/strong and related to all classic ccRCC prognostic parameters. Kaplan-Meier curves were generated to assess overall and cancer-specific survival, and multivariate analysis was performed to identify independent prognostic factors of survival. Multivariate analysis showed that MCT1 together with tumor size and TNM staging, were independently related to cancer-specific survival. MCT1, CD147, CD44 and GLUT1 expression were significantly associated with poor prognostic factors. We show that MCT1 is an independent prognostic factor for cancer-specific survival in ccRCC justifying the use of new target therapies already being tested in clinical trials.
透明细胞肾细胞癌(ccRCC)被认为是一种代谢性疾病,其特征是von Hippel-Lindau(VHL)基因缺失,导致缺氧诱导因子1α(HIF-1α)过度表达,而HIF-1α对肿瘤的发生和发展至关重要。除其他作用外,HIF-1α参与癌细胞的代谢重编程,使其向与肿瘤细胞增殖、迁移和存活相关的Warburg效应转变。在此背景下,癌细胞表达多种蛋白质,包括葡萄糖和乳酸转运蛋白以及不同的pH调节剂。其中,单羧酸转运蛋白(MCTs)尤为突出。我们的目的是全面分析ccRCC手术标本中MCT1、MCT2、MCT4、CD147、CD44、HIF-1α、GLUT1和CAIX的免疫表达情况,并将其与经典预后因素以及长期随访患者的生存率相关联。收集207例接受根治性或部分肾切除术的ccRCC患者的手术标本,用于构建组织芯片。免疫染色分为阴性/弱阳性或中度/强阳性,并与所有经典的ccRCC预后参数相关联。绘制Kaplan-Meier曲线以评估总生存率和癌症特异性生存率,并进行多因素分析以确定生存的独立预后因素。多因素分析表明,MCT1与肿瘤大小和TNM分期一起,与癌症特异性生存率独立相关。MCT1、CD147、CD44和GLUT1的表达与不良预后因素显著相关。我们发现MCT1是ccRCC患者癌症特异性生存的独立预后因素,这为目前正在临床试验中测试的新靶向治疗的应用提供了依据。