Pseudogenes may play important roles in cancer. Here, we explore the mechanism and function of a pseudogene WTAPP1 in the progress of pancreatic ductal adenocarcinoma (PDAC). WTAPP1 RNA was significantly elevated in PDAC and was associated with poor prognosis in patients. Overexpression of WTAPP1 RNA promoted PDAC proliferation and invasiveness in vitro and in vivo . Mechanistically, N 6-methyladenosine (m6A) modification stabilized WTAPP1 RNA via CCHC-type zinc finger nucleic-acid binding protein (CNBP), resulting in increased levels of WTAPP1 RNA in PDAC cells. Excessive WTAPP1 RNA bound its protein-coding counterpart WT1-associated protein (WTAP) mRNA and recruited more EIF3 translation initiation complex to promote WTAP translation. Increased WTAP protein enhanced the activation of Wnt signaling and provoked the malignant phenotypes of PDAC. Decreasing WTAPP1 RNA significantly suppressed the in vivo growth and metastasis of PDAC cell lines and patient-derived xenografts. These results indicate that m6A-mediated increases in WTAPP1 expression promote PDAC progression and thus may serve as a therapeutic target. Significance: This study reveals how aberrant m6A modification of the WTAPP1 pseudogene results in increased translation of its protein-coding counterpart to promote Wnt signaling, which contributes to pancreatic cancer progression.

中文翻译：

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N6-甲基腺苷介导的 WTAPP1 上调促进 WTAP 翻译和 Wnt 信号转导促进胰腺癌进展

假基因可能在癌症中发挥重要作用。在这里，我们探讨了假基因 WTAPP1 在胰腺导管腺癌 (PDAC) 进展中的机制和功能。WTAPP1 RNA 在 PDAC 中显着升高，并且与患者的不良预后相关。WTAPP1 RNA 的过表达促进了 PDAC 在体外和体内的增殖和侵袭。从机制上讲，N 6-甲基腺苷 (m6A) 修饰通过 CCHC 型锌指核酸结合蛋白 (CNBP) 稳定了 WTAPP1 RNA，导致 PDAC 细胞中 WTAPP1 RNA 水平升高。过多的 WTAPP1 RNA 结合其蛋白质编码对应物 WT1 相关蛋白 (WTAP) mRNA 并募集更多 EIF3 翻译起始复合物以促进 WTAP 翻译。增加的 WTAP 蛋白增强了 Wnt 信号的激活并引发了 PDAC 的恶性表型。减少 WTAPP1 RNA 可显着抑制 PDAC 细胞系和患者来源的异种移植物的体内生长和转移。这些结果表明，m6A 介导的 WTAPP1 表达增加可促进 PDAC 进展，因此可作为治疗靶点。意义：这项研究揭示了 WTAPP1 假基因的异常 m6A 修饰如何导致其蛋白质编码对应物的翻译增加以促进 Wnt 信号传导，这有助于胰腺癌的进展。