M6A-mediated up-regulation of LncRNA LIFR-AS1 enhances the progression of pancreatic cancer via miRNA-150-5p/ VEGFA/Akt signaling

Cell Cycle. 2021 Dec;20(23):2507-2518. doi: 10.1080/15384101.2021.1991122. Epub 2021 Oct 17.

Abstract

N6-methyladenosine (m6A) 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 m6A 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 m6A 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.

Keywords: LIFR-AS1; PI3K/Akt signaling; VEGFA; m6A; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Humans
  • Leukemia Inhibitory Factor Receptor alpha Subunit* / genetics
  • Leukemia Inhibitory Factor Receptor alpha Subunit* / metabolism
  • Methyltransferases* / genetics
  • Methyltransferases* / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Signal Transduction
  • Up-Regulation / genetics
  • Vascular Endothelial Growth Factor A* / genetics
  • Vascular Endothelial Growth Factor A* / metabolism

Substances

  • LIFR protein, human
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • MIRN150 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • N-methyladenosine
  • Methyltransferases
  • METTL3 protein, human
  • Proto-Oncogene Proteins c-akt
  • Adenosine

Grants and funding

This work was supported by the National Key Research and Development Program of China (2018YFC1004900 and 2018YFC1005002); Shanghai Science and Technology Committee (17ZR1427000); Shanghai Municipal Health Committee (201740156); National Natural Science Foundation of China (81772591).