Long noncoding RNA XIST regulates the EGF receptor to promote TGF-β1-induced epithelial-mesenchymal transition in pancreatic cancer

Biochem Cell Biol. 2020 Apr;98(2):267-276. doi: 10.1139/bcb-2018-0274. Epub 2019 Apr 23.

Abstract

Background: This study focuses on the lncRNA XIST (X inactive-specific transcript), an lncRNA involved in multiple human cancers, and investigates the functional significance of XIST and the molecular mechanisms underlying the epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC).

Methods: Clinical specimens from 25 patients as well as 5 human PC cell lines were analyzed for XIST, YAP, and microRNA(miR)-34a by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. To investigate how XIST influences cell proliferation, invasiveness, and apoptosis in PC, we performed the CCK-8 assays, Transwell assays, and flow cytometry. Luciferase reporter assays, qRT-PCR, and Western blot were applied to prove that miR-34a directly binds to XIST.

Results: Up-regulation of XIST and Yes associated protein (YAP) and down-regulation of miR-34a were consistently observed in the clinical specimens and PC cell lines. Silencing XIST reduced the expression of YAP and suppressed transforming growth factor (TGF)-β1-induced EMT, while over-expression of XIST increased the expression of YAP and promoted EMT. In addition, inhibition of epidermal growth factor receptor (EGFR) hampered the XIST-promoted EMT. The results from the luciferase reporter assays confirmed that miR-34a directly targets XIST and suggested that XIST regulates cell proliferation, invasiveness, and apoptosis in PC by sponging miR-34a.

Conclusions: XIST promotes TGF-β1-induced EMT by regulating the miR-34a-YAP-EGFR axis in PC.

Keywords: ARNnm long XIST; EGFR; YAP; cancer pancréatique; lncRNA XIST; miR-34a; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition*
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Male
  • MicroRNAs / metabolism
  • Neoplasm Invasiveness
  • Pancreatic Neoplasms / metabolism*
  • Phenotype
  • Prognosis
  • RNA, Long Noncoding / genetics*
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • MIRN34 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • XIST non-coding RNA
  • EGFR protein, human
  • ErbB Receptors