Servicio de Anatomía Patológica, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain.
IIS-Fundación Jiménez Diaz, C/Reyes Católicos 2, 28049, Madrid, Spain.
Br J Dermatol. 2019 Jul;181(1):114-127. doi: 10.1111/bjd.17513. Epub 2019 Mar 18.
Reprogramming of energy metabolism to enhanced aerobic glycolysis has been defined as a hallmark of cancer.
To investigate the role of the mitochondrial proteins, β-subunit of the H -ATP synthase (β-F1-ATPase), and heat-shock protein 60 (HSP60), and the glycolytic markers, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as the bioenergetic cellular (BEC) index, in melanoma progression.
The expression of energy metabolism proteins was assessed on a set of different melanoma cells representing the natural biological history of the disease: primary cultures of melanocytes, radial (WM35) and vertical (WM278) growth phases, and poorly (C81-61-PA) and highly (C8161-HA) aggressive melanoma cells. Cohorts of 63 melanocytic naevi, 55 primary melanomas and 35 metastases were used; and 113 primary melanoma and 33 metastases were used for validation.
The BEC index was significantly reduced in melanoma cells and correlated with their aggressive characteristics. Overexpression of HSP60, GAPDH and PKM2 was detected in melanoma human samples compared with naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma. The BEC index was also significantly reduced in melanoma samples and correlated with worse overall and disease-free survival; the multivariate Cox analysis showed that the BEC index (hazard ratio 0·64; 95% confidence interval 0·4-1·2) is an independent predictor for overall survival.
A profound alteration in the mitochondrial and glycolytic proteins and in the BEC index occurs in the progression of melanoma, which correlates with worse outcome, supporting that the alteration of the metabolic phenotype is crucial in melanoma transformation.
有氧糖酵解增强的能量代谢重编程已被定义为癌症的一个标志。
研究线粒体蛋白、H+-ATP 合酶的β亚基（β-F1-ATPase）和热休克蛋白 60（HSP60）以及糖酵解标志物甘油醛-3-磷酸脱氢酶（GAPDH）和丙酮酸激酶 M2（PKM2）以及生物能细胞（BEC）指数在黑色素瘤进展中的作用。
评估了一组不同的黑色素瘤细胞中能量代谢蛋白的表达，这些细胞代表了疾病的自然生物学史：黑素细胞的原代培养、放射状（WM35）和垂直（WM278）生长阶段以及低度（C81-61-PA）和高度（C8161-HA）侵袭性黑色素瘤细胞。使用了 63 个黑素细胞痣、55 个原发性黑色素瘤和 35 个转移瘤的队列；并对 113 个原发性黑色素瘤和 33 个转移瘤进行了验证。
BEC 指数在黑色素瘤细胞中显著降低，与它们的侵袭性特征相关。与痣相比，在黑色素瘤人类样本中检测到 HSP60、GAPDH 和 PKM2 的过表达，表现出从放射状生长阶段到转移性黑色素瘤表达增加的梯度。BEC 指数在黑色素瘤样本中也显著降低，与总生存率和无病生存率较差相关；多变量 Cox 分析显示，BEC 指数（危险比 0.64；95%置信区间 0.4-1.2）是总生存率的独立预测因子。
在黑色素瘤的进展中，线粒体和糖酵解蛋白以及 BEC 指数发生了深刻的改变，这与预后较差相关，支持代谢表型的改变在黑色素瘤转化中至关重要。
