Pancreatic cancer is a leading cause of cancer-related death worldwide. Cisplatin is an essential drug treating patients with BRCA1/2 or PALB2 mutations. Whether other genetic determinants of cisplatin sensitivity exist and their underlying mechanisms remain unclear.

Immunohistochemistry was used to determine METTL14 expression in pancreatic cancer tissues and non-tumoural tissues. Cell proliferation was detected with CCK-8 assays. Apoptosis was analysed via Western blotting and flow cytometry, and autophagy was analysed via Western blotting and immunofluorescence.

In this work, we found higher METTL14 expression in pancreatic cancer tissues than in non-tumoural tissues, and METTL14 expression was associated with pathological characteristics. Downregulation of METTL14 with siRNA sensitized pancreatic cancer cells to cisplatin. Specifically, apoptosis and autophagy were significantly enhanced in METT14 knockdown cells compared with control cells after treatment with cisplatin. Mechanistically, the AMPKα, ERK1/2 and mTOR signalling pathways were disturbed by downregulation of METTL14. We further found that METTL14 knockdown-mediated autophagy was dependent on mTOR signalling and that mTOR activation decreased autophagy to the level observed in the control group. Collectively, our results indicate that METTL14 is upregulated in pancreatic cancer, downregulation of METTL14 sensitizes pancreatic cancer cells to cisplatin by enhancing apoptosis, and autophagy is improved via an mTOR signalling-dependent pathway.

胰腺癌是全球范围内与癌症相关的死亡的主要原因。顺铂是治疗具有BRCA1 / 2或PALB2突变的患者的基本药物。顺铂敏感性的其他遗传决定因素是否存在及其潜在机制尚不清楚。

免疫组织化学用于确定胰腺癌组织和非肿瘤组织中METTL14的表达。用CCK-8测定法检测细胞增殖。通过蛋白质印迹和流式细胞术分析细胞凋亡，并通过蛋白质印迹和免疫荧光分析自噬。

在这项工作中，我们发现胰腺癌组织中METTL14的表达高于非肿瘤组织，且METTL14的表达与病理特征有关。siRNA使胰腺癌细胞对顺铂的METTL14下调。具体而言，与顺铂处理后的对照细胞相比，METT14敲低细胞的凋亡和自噬显着增强。从机理上讲，AMPKα，ERK1 / 2和mTOR信号通路受到METTL14下调的干扰。我们进一步发现，METTL14敲低介导的自噬依赖于mTOR信号传导，而mTOR激活将自噬降低至对照组中观察到的水平。总的来说，我们的结果表明METTL14在胰腺癌中上调，