Department of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Cell Death Dis. 2021 Apr 1;12(4):347. doi: 10.1038/s41419-021-03641-8.
Papillary thyroid carcinoma (PTC) is one of the most common kinds of endocrine-related cancer and has a heterogeneous prognosis. Metabolic reprogramming is one of the hallmarks of cancers. Aberrant glucose metabolism is associated with malignant biological behavior. However, the functions and mechanisms of glucose metabolism genes in PTC are not fully understood. Thus, data from The Cancer Genome Atlas database were analyzed, and lactate dehydrogenase A (LDHA) was determined to be a potential novel diagnostic and therapeutic target for PTCs. The research objective was to investigate the expression of LDHA in PTCs and to explore the main functions and relative mechanisms of LDHA in PTCs. Higher expression levels of LDHA were found in PTC tissues than in normal thyroid tissues at both the mRNA and protein levels. Higher expression levels of LDHA were correlated with aggressive clinicopathological features and poor prognosis. Moreover, we found that LDHA not only promoted PTC migration and invasion but also enhanced tumor growth both in vitro and in vivo. In addition, we revealed that the metabolic products of LDHA catalyzed induced the epithelial-mesenchymal transition process by increasing the relative gene H3K27 acetylation. Moreover, LDHA knockdown activated the AMPK pathway and induced protective autophagy. An autophagy inhibitor significantly enhanced the antitumor effect of FX11. These results suggested that LDHA enhanced the cell metastasis and proliferation of PTCs and may therefore become a potential therapeutic target for PTCs.
甲状腺乳头状癌（PTC）是最常见的内分泌相关癌症之一，具有异质性的预后。代谢重编程是癌症的标志之一。异常的葡萄糖代谢与恶性生物学行为有关。然而，葡萄糖代谢基因在 PTC 中的功能和机制尚不完全清楚。因此，对癌症基因组图谱数据库中的数据进行了分析，发现乳酸脱氢酶 A（LDHA）可能是 PTC 的潜在新型诊断和治疗靶点。本研究旨在探讨 LDHA 在 PTC 中的表达，并探讨 LDHA 在 PTC 中的主要功能和相关机制。结果发现，LDHA 在 PTC 组织中的 mRNA 和蛋白水平均高于正常甲状腺组织。LDHA 的高表达与侵袭性临床病理特征和不良预后相关。此外，我们发现 LDHA 不仅促进了 PTC 的迁移和侵袭，而且在体外和体内均增强了肿瘤的生长。此外，我们揭示了 LDHA 催化的代谢产物通过增加相对基因 H3K27 乙酰化诱导上皮-间充质转化过程。此外，LDHA 敲低激活了 AMPK 通路并诱导保护性自噬。自噬抑制剂显著增强了 FX11 的抗肿瘤作用。这些结果表明，LDHA 增强了 PTC 的细胞转移和增殖能力，因此可能成为 PTC 的潜在治疗靶点。
