PLA2G16 is a member of the phospholipase family that catalyses the generation of lysophosphatidic acids (LPAs) and free fatty acids (FFAs) from phosphatidic acid. In the current study, we explored the functional role of PLA2G16 in pancreatic adenocarcinoma (PAAD) and the genetic/epigenetic alterations leading to its dysregulation. Bioinformatic analysis was performed using data from The Cancer Genome Atlas (TCGA), Genotype‐Tissue Expression (GTEx) and the Human Protein Atlas (HPA). Then, PANC‐1 and MIA‐PaCa‐2 cells harbouring TP53 mutations were used for cellular and animal studies. Results showed that PL2G16 expression was significantly up‐regulated in PAAD tissue and was associated with unfavourable survival. PLA2G16 inhibition suppressed pancreatic cell growth in vitro and in vivo and also inhibited aerobic glycolysis. Bioinformatic analysis indicated that KLF5 was positively correlated with PLA2G16 expression in PAAD tumours with TP53 mutation. TP53 or KLF5 inhibition significantly reduced PLA2G16 expression at both mRNA and protein levels. Dual‐luciferase and chromatin Immunoprecipitation‐quantitative polymerase chain reaction assays showed that KLF5 directly bound to the PLA2G16 promoter and activated its transcription. Co‐immunoprecipitation assay indicated that mutant p53 had a physical interaction with KLF5. Inhibition of mutant p53 impaired the transcriptional activating effects of KLF5. In PAAD cases in TCGA, PLA2G16 expression was positively correlated with its copy number (Pearson's r = 0.51, P < 0.001), but was strongly and negatively correlated with the methylation level of cg09518969 (Pearson's r = −0.64, P < 0.001), a 5’‐cytosine‐phosphodiester bond‐guanine‐3’ site within its gene locus. In conclusion, this study revealed a novel mutant p53/KLF5‐PLA2G16 regulatory axis on tumour growth and glycolysis in PAAD.

中文翻译：

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PLA2G16是突变的p53 / KLF5转录靶标，可促进胰腺癌的糖酵解。

PLA2G16是磷脂酶家族的成员，该酶催化从磷脂酸生成溶血磷脂酸（LPA）和游离脂肪酸（FFA）。在当前的研究中，我们探讨了PLA2G16在胰腺腺癌（PAAD）中的功能性作用以及导致其失调的遗传/表观遗传学改变。使用癌症基因组图谱（TCGA），基因型组织表达（GTEx）和人类蛋白质图谱（HPA）的数据进行了生物信息学分析。然后，将带有TP53突变的PANC-1和MIA-PaCa-2细胞用于细胞和动物研究。结果表明，PAAD组织中PL2G16的表达明显上调，并且与不良的生存有关。PLA2G16抑制作用抑制了胰腺细胞在体外和体内的生长，并且还抑制了有氧糖酵解。生物信息学分析表明，在具有TP53突变的PAAD肿瘤中，KLF5与PLA2G16的表达呈正相关。TP53或KLF5抑制显着降低PLA2G16在mRNA和蛋白质水平上的表达。双荧光素酶和染色质免疫沉淀-定量聚合酶链反应分析表明，KLF5直接与PLA2G16启动子结合并激活其转录。免疫共沉淀分析表明，突变体p53与KLF5有物理相互作用。突变体p53的抑制削弱了KLF5的转录激活作用。在TCGA中的PAAD病例中，PLA2G16的表达与其拷贝数呈正相关（Pearson的r  = 0.51，P  <0.001），而与cg09518969的甲基化水平呈正相关（Pearson的r  = −0.64，P） <0.001），其基因座中有一个5'-胞嘧啶-磷酸二酯键-鸟嘌呤-3'位点。总之，这项研究揭示了一种新型的突变型p53 / KLF5-PLA2G16调控轴，可调控PAAD中的肿瘤生长和糖酵解。