Department of Digestive Internal, Yangpu Shidong Hospital, Anhui Medical University, Shanghai, China.
National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Cell Cycle. 2021 Dec;20(23):2507-2518. doi: 10.1080/15384101.2021.1991122. Epub 2021 Oct 17.
N-methyladenosine (mA) modification, the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing. There is extensive evidence indicating that long non-coding RNAs (lncRNAs) serve as key regulators of oncogenesis and tumor progression in humans. Through prior study has assessed that LIFR-AS1 plays a key role in various kinds of malignant tumors. However, the exact role of mA induced LIFR-AS1 in pancreatic cancer (PC) and its potential molecular mechanisms remain largely unknown. In this study, we determined that PC cell lines and tumors exhibit increased LIFR-AS1 expression that correlates with larger tumor size, lymph node metastasis, and more advanced TNM stage. Functionally, loss-of-function studies indicated that LIFR-AS1 knockdown decreased the proliferation, migration, and invasion of PC cells in vitro. Mechanistically, we found that METTL3 induced mA hyper-methylation on the 3' UTR of LIFR-AS1 to enhance its mRNA stability and LIFR-AS1 could directly interact with miR-150-5p, thereby indirectly up-regulating VEGFA expressions within cells. Through rescue experiments, we were able to confirm that the unfavorable impact of LIFR-AS1 knockdown on VEGFA /PI3K/Akt Signaling could be reversed via the inhibition of miR-150-5p expression. Together, these findings indicate that a noval m6A-LIFR-AS1 axis promotes PC progression at least in part via regulation of the miR-150-5p/VEGFA axis, indicating that this regulatory axis may be a viable clinical target for the treatment of PC.
N6-甲基腺苷（m6A）修饰是真核 RNA 转录本中最丰富的内部甲基化修饰，对 RNA 加工具有重要影响。有大量证据表明，长非编码 RNA（lncRNA）在人类肿瘤发生和肿瘤进展中起关键调节作用。先前的研究已经评估了 LIFR-AS1 在各种恶性肿瘤中发挥关键作用。然而，m6A 诱导的 LIFR-AS1 在胰腺癌（PC）中的确切作用及其潜在的分子机制在很大程度上仍然未知。在本研究中，我们确定 PC 细胞系和肿瘤中 LIFR-AS1 的表达增加，与更大的肿瘤大小、淋巴结转移和更晚期的 TNM 分期相关。功能丧失研究表明，LIFR-AS1 敲低降低了 PC 细胞的体外增殖、迁移和侵袭能力。在机制上，我们发现 METTL3 诱导 LIFR-AS1 的 3'UTR 上的 m6A 过度甲基化，增强其 mRNA 稳定性，并且 LIFR-AS1 可以直接与 miR-150-5p 相互作用，从而间接上调细胞内 VEGFA 的表达。通过挽救实验，我们能够证实 LIFR-AS1 敲低对 VEGFA/PI3K/Akt 信号通路的不利影响可以通过抑制 miR-150-5p 的表达来逆转。总之，这些发现表明，一种新的 m6A-LIFR-AS1 轴至少部分通过调节 miR-150-5p/VEGFA 轴促进 PC 进展，表明该调节轴可能是治疗 PC 的可行临床靶点。
