Aerobic glycolysis, also known as the Warburg effect, is emerged as a hallmark of most cancer cells. Increased aerobic glycolysis is closely associated with tumor aggressiveness and predicts a poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent genomic aberrations and increased glycolytic phenotype. However, the detailed molecular events implicated in aerobic glycolysis of PDAC are not well understood. In this study, we performed a comprehensive molecular characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis of 89 informative PDAC tumors identified substantial copy number variations (MYC, GATA6, FGFR1, IDO1, and SMAD4) and mutations (KRAS, SMAD4, and RNF43) related to aerobic glycolysis. Moreover, integrated analysis of transcriptional profiles revealed many differentially expressed long non-coding RNAs involved in PDAC aerobic glycolysis. Loss-of-function studies showed that LINC01559 and UNC5B-AS1 knockdown significantly inhibited the glycolytic capacity of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate. Moreover, genetic silencing of LINC01559 and UNC5B-AS1 suppressed tumor growth and resulted in alterations in several signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, and transcriptional misregulation in cancer. Notably, high expression of LINC01559 and UNC5B-AS1 predicted poor patient prognosis and correlated with the maximum standard uptakevalue (SUVmax) in PDAC patients who received preoperative ¹⁸F-FDG PET/CT. Taken together, our results decipher the glycolysis-associated copy number variations, mutations, and lncRNA landscapes in PDAC. These findings improve our knowledge of the molecular mechanism of PDAC aerobic glycolysis and may have practical implications for precision cancer therapy.

中文翻译：

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破译有氧糖酵解的基因组和 lncRNA 图谱确定了胰腺癌的潜在治疗靶点

有氧糖酵解，也称为 Warburg 效应，是大多数癌细胞的标志。有氧糖酵解增加与肿瘤侵袭性密切相关，预示着预后不良。胰腺导管腺癌 (PDAC) 的特征是显着的基因组畸变和糖酵解表型增加。然而，与 PDAC 有氧糖酵解有关的详细分子事件尚不清楚。在这项研究中，我们使用来自癌症基因组图谱 (TCGA) 的多维“组学”数据进行了全面的分子表征。对 89 个提供信息的 PDAC 肿瘤的详细分析确定了大量拷贝数变异（MYC、GATA6、FGFR1、IDO1和SMAD4）和突变（KRAS、SMAD4和RNF43) 与有氧糖酵解有关。此外，转录谱的综合分析揭示了许多参与 PDAC 有氧糖酵解的差异表达的长非编码 RNA。功能丧失研究表明，LINC01559 和 UNC5B-AS1 敲低显着抑制了 PDAC 细胞的糖酵解能力，如葡萄糖摄取、乳酸产生和细胞外酸化率降低所揭示的。此外，LINC01559 和 UNC5B-AS1 的基因沉默抑制了肿瘤生长并导致了几种信号通路的改变，例如 TNF 信号通路、IL-17 信号通路和癌症中的转录失调。值得注意的是，LINC01559 和 UNC5B-AS1 的高表达预示着患者预后不良，并与术前接受治疗的 PDAC 患者的最大标准摄取值 (SUVmax) 相关。¹⁸ F-FDG PET/CT。总之，我们的结果破译了 PDAC 中与糖酵解相关的拷贝数变异、突变和 lncRNA 景观。这些发现提高了我们对 PDAC 有氧糖酵解分子机制的认识，并可能对精准癌症治疗具有实际意义。