NPAS2 通过 HIF-1A 信号促进前列腺癌的有氧糖酵解和肿瘤生长。
NPAS2 promotes aerobic glycolysis and tumor growth in prostate cancer through HIF-1A signaling.
机构信息
Department of Urology, The First Affiliated Hospital of Air Force Medical University, 127 Changle West Road, 710032, Xi 'an, Shaanxi, China.
Department of Human Movement Science, Xi'an Physical Education University, Xi'an, China.
出版信息
BMC Cancer. 2023 Mar 28;23(1):280. doi: 10.1186/s12885-023-10685-w.
BACKGROUND
Prostate cancer (PCa), one of the common malignant tumors, is the second leading cause of cancer-related deaths in men. The circadian rhythm plays a critical role in disease. Circadian disturbances are often found in patients with tumors and enable to promote tumor development and accelerate its progression. Accumulating evidence suggests that the core clock gene NPAS2 (neuronal PAS domain-containing protein 2) has been implicated in tumors initiation and progression. However, there are few studies on the association between NPAS2 and prostate cancer. The purpose of this paper is to investigate the impact of NPAS2 on cell growth and glucose metabolism in prostate cancer.
METHODS
Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining, western blot, GEO (Gene Expression Omnibus) and CCLE (Cancer Cell Line Encyclopedia) databases were used to analyze the expression of NPAS2 in human PCa tissues and various PCa cell lines. Cell proliferation was assessed using MTS, clonogenic assays, apoptotic analyses, and subcutaneous tumor formation experiments in nude mice. Glucose uptake, lactate production, cellular oxygen consumption rate and medium pH were measured to examine the effect of NPAS2 on glucose metabolism. The relation of NPAS2 and glycolytic genes was analyzed based on TCGA (The Cancer Genome Atlas) database.
RESULTS
Our data showed that NPAS2 expression in prostate cancer patient tissue was elevated compared with that in normal prostate tissue. NPAS2 knockdown inhibited cell proliferation and promoted cell apoptosis in vitro and suppressed tumor growth in a nude mouse model in vivo. NPAS2 knockdown led to glucose uptake and lactate production diminished, oxygen consumption rate and pH elevated. NPAS2 increased HIF-1A (hypoxia-inducible factor-1A) expression, leading to enhanced glycolytic metabolism. There was a positive correlation with the expression of NPAS2 and glycolytic genes, these genes were upregulated with overexpression of NPAS2 while knockdown of NPAS2 led to a lower level.
CONCLUSION
NPAS2 is upregulated in prostate cancer and promotes cell survival by promoting glycolysis and inhibiting oxidative phosphorylation in PCa cells.
背景
前列腺癌（PCa）是常见的恶性肿瘤之一，是男性癌症相关死亡的第二大主要原因。昼夜节律在疾病中起着关键作用。肿瘤患者常出现昼夜节律紊乱，促进肿瘤发生发展，加速其进展。越来越多的证据表明，核心钟基因 NPAS2（神经元 PAS 结构域蛋白 2）参与了肿瘤的发生和发展。然而，关于 NPAS2 与前列腺癌的关系研究甚少。本文旨在探讨 NPAS2 对前列腺癌细胞生长和葡萄糖代谢的影响。
方法
采用实时定量 PCR（qRT-PCR）、免疫组织化学（IHC）染色、Western blot、GEO（基因表达综合数据库）和 CCLE（癌症细胞系百科全书）数据库分析 NPAS2 在人前列腺癌组织和各种前列腺癌细胞系中的表达。采用 MTS、集落形成实验、凋亡分析和裸鼠皮下肿瘤形成实验评估细胞增殖。检测葡萄糖摄取、乳酸生成、细胞耗氧率和培养基 pH 值，以研究 NPAS2 对葡萄糖代谢的影响。基于 TCGA（癌症基因组图谱）数据库分析 NPAS2 与糖酵解基因的关系。
结果
我们的数据表明，与正常前列腺组织相比，前列腺癌患者组织中 NPAS2 的表达升高。NPAS2 敲低抑制了体外细胞增殖并促进了细胞凋亡，抑制了体内裸鼠模型中的肿瘤生长。NPAS2 敲低导致葡萄糖摄取和乳酸生成减少，耗氧率和 pH 值升高。NPAS2 增加了 HIF-1A（缺氧诱导因子 1A）的表达，促进了糖酵解代谢。NPAS2 与糖酵解基因的表达呈正相关，NPAS2 过表达时这些基因上调，而 NPAS2 敲低时则下调。
结论
NPAS2 在前列腺癌中上调，通过促进糖酵解和抑制 PCa 细胞中的氧化磷酸化来促进细胞存活。
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