Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Reproductive Medical Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Cell Transplant. 2022 Jan-Dec;31:9636897221122997. doi: 10.1177/09636897221122997.
Accumulating data show that N6-methyladenosine (mA) methyltransferase METTL3 and long noncoding RNA MALAT1 act pivotal roles in multiple malignancies including prostate cancer (PCa). However, the role and molecular mechanism underlying METTL3-mediated mA modification of MALAT1 in PCa remain undocumented. The association of METTL3 and MALAT1 expression with clinicopathological characteristics and prognosis in patients with PCa was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and public The Cancer Genome Atlas (TCGA) dataset. The and experiments were executed to investigate the role of METTL3 in PCa. mA dot blot, methylated RNA immunoprecipitation (MeRIP), RIP, and qRT-PCR assays were employed to observe METTL3-mediated mA modification of MALAT1. The effects of METTL3 on MALAT1-mediated PI3K/AKT pathway were assessed by Western blot analysis. As a result, we found that METTL3 was significantly upregulated in PCa tissues and high expression of METTL3 was associated with Gleason score and tumor recurrence in patients with PCa. Knockdown of METTL3 markedly repressed growth and invasion of PCa cells and , whereas ectopic expression of METTL3 showed the opposite effects. Moreover, knockdown of METTL3 decreased the total mA levels of PCa cells as well as the MALAT1 mA levels, leading to reduced MALAT1 expression. Overexpression of MALAT1 reversed METTL3 knockdown-induced antitumor effects and PI3K/AKT signaling inactivation. MALAT1 harbored a positive correlation with METTL3 expression and tumor recurrence in PCa. In conclusion, our findings demonstrate that METTL3-mediated mA modification of lncRNA MALAT1 promotes growth and invasion of PCa cells by activating PI3K/AKT signaling.
越来越多的证据表明，N6-甲基腺苷（m6A）甲基转移酶 METTL3 和长链非编码 RNA MALAT1 在包括前列腺癌（PCa）在内的多种恶性肿瘤中发挥关键作用。然而，METTL3 介导的 MALAT1 m6A 修饰在 PCa 中的作用和分子机制尚不清楚。通过实时定量聚合酶链反应（qRT-PCR）、Western blot 和公共的癌症基因组图谱（TCGA）数据集分析了 METTL3 和 MALAT1 表达与 PCa 患者临床病理特征和预后的相关性。通过 、 实验研究了 METTL3 在 PCa 中的作用。m6A 斑点印迹、甲基化 RNA 免疫沉淀（MeRIP）、RIP 和 qRT-PCR 实验用于观察 METTL3 介导的 MALAT1 m6A 修饰。通过 Western blot 分析评估了 METTL3 对 MALAT1 介导的 PI3K/AKT 通路的影响。结果发现，METTL3 在 PCa 组织中显著上调，METTL3 高表达与前列腺癌患者的 Gleason 评分和肿瘤复发有关。METTL3 的敲低显著抑制了 PCa 细胞的生长和侵袭 、 ，而 METTL3 的异位表达则表现出相反的效果。此外，METTL3 的敲低降低了 PCa 细胞的总 m6A 水平以及 MALAT1 的 m6A 水平，导致 MALAT1 表达降低。MALAT1 的过表达逆转了 METTL3 敲低引起的抗肿瘤作用和 PI3K/AKT 信号失活。MALAT1 与 PCa 中的 METTL3 表达和肿瘤复发呈正相关。综上所述，我们的研究结果表明，METTL3 介导的 lncRNA MALAT1 的 m6A 修饰通过激活 PI3K/AKT 信号促进 PCa 细胞的生长和侵袭。
