Gao Wei, Hu Lingyin, Zhang Minjuan, Liu Shuai, Xu Shaowei, Chow Velda Ling-Yu, Chan Jimmy Yu-Wai, Wong Thian-Sze
Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong 21 Sassoon Road, Pokfulam, Hong Kong, China.
Department of Head and Neck Surgery, Cancer Hospital of Shantou University Medical College 7 Raoping Road, Shantou 515031, Guangdong Province, China.
Am J Cancer Res. 2022 Jan 15;12(1):48-67. eCollection 2022.
Oral tongue squamous cell carcinoma (OTSCC) was one of the most hypoxic tumors with unfavorable outcomes. Hypoxia-inducible factor-1 (HIF-1) signaling was associated with cancer proliferation, lymph node metastasis, angiogenesis and poor prognosis of OTSCC. Dihydroorotate dehydrogenase (DHODH) catalyzed the rate-limiting step in the de novo pyrimidine biosynthesis. The aim of the study was to explore the biological function of DHODH and investigate whether DHODH regulated HIF-1 signaling in OTSCC. Proliferation, migration and anoikis resistance were used to determine the function of DHODH. Western blot and luciferase activity assays were used to determine the regulatory role of DHODH on HIF-1. We found that increased DHODH expression was associated with advanced tumor stage and poorly differentiated tumor in head and neck cancer patients in The Cancer Genome Atlas (TCGA). DHODH enhanced the proliferation and aggressiveness of OTSCC. Moreover, DHODH prompted tumor growth and metastasis . DHODH promoted transcription, protein stability, and transactivation activity of HIF1A. DHODH-induced HIF1A upregulation in OTSCC can be reversed by reactive oxygen species (ROS) scavenger, indicating that DHODH enhanced HIF1A expression via ROS production. DHODH inhibitor suppressed DHODH-mediated ROS generation and HIF1A upregulation. Targeting DHODH using clinically available inhibitor, atovaquone, might provide a new strategy to treat OTSCC.
口腔舌鳞状细胞癌（OTSCC）是预后较差的缺氧肿瘤之一。缺氧诱导因子-1（HIF-1）信号通路与OTSCC的癌症增殖、淋巴结转移、血管生成及不良预后相关。二氢乳清酸脱氢酶（DHODH）催化嘧啶从头生物合成的限速步骤。本研究旨在探讨DHODH的生物学功能，并研究其是否在OTSCC中调节HIF-1信号通路。通过增殖、迁移和失巢凋亡抗性来确定DHODH的功能。采用蛋白质免疫印迹法和荧光素酶活性测定法来确定DHODH对HIF-1的调控作用。我们发现，在癌症基因组图谱（TCGA）中，头颈部癌患者中DHODH表达增加与肿瘤分期进展及肿瘤低分化相关。DHODH增强了OTSCC的增殖和侵袭性。此外，DHODH促进肿瘤生长和转移。DHODH促进HIF1A的转录、蛋白质稳定性及反式激活活性。OTSCC中DHODH诱导的HIF1A上调可被活性氧（ROS）清除剂逆转，表明DHODH通过产生ROS增强HIF1A表达。DHODH抑制剂可抑制DHODH介导的ROS生成及HIF1A上调。使用临床可用抑制剂阿托伐醌靶向DHODH可能为治疗OTSCC提供一种新策略。
