Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S1W17, Chuo-ku, Sapporo, 060-8556, Japan.
Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S1W16, Chuo-ku, Sapporo, 060-8543, Japan.
BMC Cancer. 2023 Jan 25;23(1):85. doi: 10.1186/s12885-022-10433-6.
While molecular targeted drugs and other therapies are being developed for many tumors, pancreatic cancer is still considered to be the malignant tumor with the worst prognosis. We started this study to identify prognostic genes and therapeutic targets of pancreatic cancer.
To comprehensively identify prognostic genes in pancreatic cancer, we investigated the correlation between gene expression and cancer-specific prognosis using transcriptome and clinical information datasets from The Cancer Genome Atlas (TCGA). In addition, we examined the effects of the suppression of candidate prognostic genes in pancreatic cancer cell lines.
We found that patients with high expression levels of MYEOV, a primate-specific gene with unknown function, had significantly shorter disease-specific survival times than those with low expression levels. Cox proportional hazards analysis revealed that high expression of MYEOV was significantly associated with poor survival and was an independent prognostic factor for disease-specific survival in pancreatic cancer patients. Analysis of multiple cancer samples revealed that the MYEOV promoter region is methylated in noncancer tissues but is demethylated in tumors, causing MYEOV overexpression in tumors. Notably, the knockdown of MYEOV suppressed the expression of MTHFD2 and other folate metabolism-related enzyme genes required for the synthesis of amino acids and nucleic acids and also restored the expression of c-Myc and mTORC1 repressors.
There is a significant correlation between elevated MYEOV expression and poor disease-specific survival in pancreatic cancer patients. MYEOV enhances the activation of several oncogenic pathways, resulting in the induction of pancreatic cancer cell proliferation. Overall, MYEOV acts as an oncogene in pancreatic cancer. Furthermore, MYEOV may be a prognostic biomarker and serve as an 'actionable' therapeutic target for pancreatic cancers.
虽然许多肿瘤都在开发分子靶向药物和其他疗法，但胰腺癌仍被认为是预后最差的恶性肿瘤。我们开始这项研究是为了确定胰腺癌的预后基因和治疗靶点。
为了全面鉴定胰腺癌的预后基因，我们使用来自癌症基因组图谱（TCGA）的转录组和临床信息数据集，研究基因表达与癌症特异性预后之间的相关性。此外，我们还检查了候选预后基因在胰腺癌细胞系中的抑制作用。
我们发现，表达水平较高的 MYEOV（一种功能未知的灵长类特异性基因）的患者与表达水平较低的患者相比，疾病特异性生存时间明显缩短。Cox 比例风险分析显示，MYEOV 的高表达与不良预后显著相关，是胰腺癌患者疾病特异性生存的独立预后因素。对多个癌症样本的分析表明，MYEOV 启动子区域在非癌组织中被甲基化，但在肿瘤中被去甲基化，导致肿瘤中 MYEOV 的过表达。值得注意的是，MYEOV 的敲低抑制了 MTHFD2 和其他叶酸代谢相关酶基因的表达，这些基因对于氨基酸和核酸的合成是必需的，同时也恢复了 c-Myc 和 mTORC1 抑制剂的表达。
在胰腺癌患者中，MYEOV 表达升高与疾病特异性生存率降低显著相关。MYEOV 增强了几条致癌途径的激活，导致胰腺癌细胞增殖的诱导。总的来说，MYEOV 是胰腺癌中的一种癌基因。此外，MYEOV 可能是一种预后生物标志物，并可作为胰腺癌的“可操作”治疗靶点。
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