Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan Hubei Province, China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-most) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan Hubei Province, China.
Epigenetics. 2022 Dec;17(12):1738-1752. doi: 10.1080/15592294.2022.2061117. Epub 2022 Apr 11.
Pancreatic cancer (PC) is one of the most fatal cancers with a very poor prognosis. Here, we found that N-methyladenosine (mA) RNA demethylase fat mass and obesity-related protein (FTO) promote the growth, migration and invasion of PC. FTO expression level is increased in human PC and is associated with poor prognosis of PC patients. Knockdown of FTO increases mA methylation of TFPI-2 mRNA in PC cells, thereby increasing mRNA stability via the mA reader YTHDF1, resulting in up-regulation of TFPI-2 expression, and inhibits PC proliferation, colony formation, sphere formation, migration and invasion , as well as tumour growth . Rescue assay further confirms that FTO facilitates cancer progression by reducing the expression of TFPI-2. Mechanistically, FTO promotes the progression of PC at least partially through reducing mA/YTHDF1 mediated TFPI-2 mRNA stability. Our findings reveal that FTO, as an mA demethylase, plays a critical role in promoting PC growth, migration and invasion, suggesting that FTO may be a potential therapeutic target for treating PC.
胰腺癌（PC）是预后最差的致命癌症之一。在这里，我们发现 N6-甲基腺苷（m6A）RNA 去甲基酶肥胖相关蛋白（FTO）促进 PC 的生长、迁移和侵袭。FTO 在人 PC 中的表达水平增加，与 PC 患者的预后不良相关。FTO 敲低可增加 PC 细胞中 TFPI-2 mRNA 的 m6A 甲基化，从而通过 m6A 阅读器 YTHDF1 增加 mRNA 稳定性，导致 TFPI-2 表达上调，抑制 PC 增殖、集落形成、球体形成、迁移和侵袭，以及肿瘤生长。挽救实验进一步证实，FTO 通过降低 TFPI-2 的表达促进癌症进展。从机制上讲，FTO 至少部分通过降低 m6A/YTHDF1 介导的 TFPI-2 mRNA 稳定性促进 PC 的进展。我们的研究结果表明，FTO 作为一种 m6A 去甲基酶，在促进 PC 生长、迁移和侵袭中发挥关键作用，提示 FTO 可能是治疗 PC 的潜在治疗靶点。
