The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4

<i>BRAF</i> mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. <i>BRAF</i> mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. <i>NRAS</i> mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.

BRAF基因突变（BRAF）是已知的黑色素瘤发生驱动因素，近期研究还发现其参与瓦博格效应（Warburg effect）；而这种能量代谢重编程已被视作黑色素瘤患者的潜在治疗策略。因此，本研究旨在评估一组糖酵解代谢相关蛋白在一系列黑色素瘤样本中的表达特征及其预后价值。本研究对356例黑色素瘤患者与20例良性痣患者的样本开展免疫组化检测，目标蛋白包括单羧酸转运蛋白1（MCT1）、单羧酸转运蛋白4（MCT4）、葡萄糖转运蛋白1（GLUT1）及碳酸酐酶IX（CAIX）。纳入研究的样本涵盖20例良性痣组织、282例原发性黑色素瘤组织、117例淋巴结转移灶样本及54例远处转移灶样本。在92例黑色素瘤患者中，29例检出BRAF突变（占比31.5%）；20例良性痣样本中则检出17例该突变（占比85%）。NRAS基因突变（NRAS）的检出情况为：36例黑色素瘤患者中检出4例（占比11.1%），19例良性痣样本中检出1例（占比5.3%）。研究结果显示，转移灶样本中MCT4与GLUT1的表达水平显著升高，且MCT1、MCT4及GLUT1的表达与不良预后变量显著相关。值得注意的是，MCT1与MCT4的高表达与更短的总生存期（overall survival）显著相关。综上，本研究为黑色素瘤的代谢机制研究提供了全新视角，为新型靶向治疗手段的开发铺平了道路。