Liu Chien-Liang, Yang Po-Sheng, Wang Tao-Yeuan, Huang Shih-Yuan, Kuo Yi-Hue, Cheng Shih-Ping
Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan.
Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
J Cancer. 2019 Jun 9;10(16):3819-3829. doi: 10.7150/jca.30018. eCollection 2019.
Increased aerobic glycolysis portends an unfavorable prognosis in thyroid cancer. The metabolic reprogramming likely results from altered mitochondrial activity and may promote cancer progression. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) plays a pivotal role in mitochondrial biogenesis and function. In the present study, we aimed to evaluate the clinicopathological significance of PGC1α expression and the potential effects of PGC1α modulation. Firstly, the expression of PGC1α in thyroid cancer samples was evaluated using western blot analysis and immunohistochemical staining. Compared with normal thyroid tissue, PGC1α expression was downregulated in thyroid cancer. PGC1α-negative papillary cancer was associated with BRAF V600E mutation, large tumor size, extrathyroidal or lymphovascular invasion, lymph node metastasis, and advanced stage. The results were consistent with the analysis of The Cancer Genome Atlas data. PGC1α expression correlated with oxygen consumption in thyroid cancer cells and was inversely related to AKT activity. The biologic relevance of PGC1α was further investigated by gain- and loss-of-function experimental studies. PGC1α overexpression led to augmented oxidative metabolism and accelerated tumor growth, whereas PGC1α knockdown induced a glycolytic phenotype but reduced tumor growth in vivo. In conclusion, PGC1α downregulation is associated with glycolytic metabolism and advanced disease in thyroid cancer. Nonetheless, manipulating PGC1α expression and metabolic phenotype does not necessarily translate into beneficial effects. It suggests that the metabolic phenotype is likely the consequence rather than the cause of disease progression in thyroid cancer.
有氧糖酵解增加预示着甲状腺癌预后不良。这种代谢重编程可能源于线粒体活性改变，并可能促进癌症进展。过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）在线粒体生物发生和功能中起关键作用。在本研究中，我们旨在评估PGC1α表达的临床病理意义以及PGC1α调节的潜在影响。首先，使用蛋白质免疫印迹分析和免疫组织化学染色评估甲状腺癌样本中PGC1α的表达。与正常甲状腺组织相比，甲状腺癌中PGC1α表达下调。PGC1α阴性的乳头状癌与BRAF V600E突变、肿瘤体积大、甲状腺外或淋巴管侵犯、淋巴结转移及晚期相关。结果与癌症基因组图谱数据的分析一致。PGC1α表达与甲状腺癌细胞的耗氧量相关，与AKT活性呈负相关。通过功能获得和功能丧失实验研究进一步探究了PGC1α的生物学相关性。PGC1α过表达导致氧化代谢增强和肿瘤生长加速，而敲低PGC1α诱导糖酵解表型，但在体内降低肿瘤生长。总之，PGC1α下调与甲状腺癌的糖酵解代谢和疾病进展相关。尽管如此，操纵PGC1α表达和代谢表型不一定会产生有益效果。这表明代谢表型可能是甲状腺癌疾病进展的结果而非原因。
