DC-SIGN mediates gastric cancer progression by regulating the JAK2/STAT3 signaling pathway and affecting LncRNA RP11-181G12.2 expression

Biomed Pharmacother. 2020 Jan:121:109644. doi: 10.1016/j.biopha.2019.109644. Epub 2019 Nov 19.

Abstract

Background: The molecular mechanisms of gastric cancer (GC) development are very complicated. Recent studies revealed that DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein (DC-SIGNR) is involved in colon cancer and GC biological processes. However, the exact roles of DC-SIGN in GC remain unrevealed.

Methods: DC-SIGN overexpression and knockdown experiments were performed by using DC-SIGN shRNA or DC-SIGN plasmid to investigate the biological roles of DC-SIGN in proliferation, cell cycle progression, migration and invasion of GC cells in vitro. Furthermore, the lncRNA profiles of SGC-7901 cells with control shRNA and DC-SIGN shRNA were generated by using microarray analysis. Mechanistically, the relationship between DC-SIGN, RP11-181G12.2 and the JAK2/STAT3 signaling pathway was then investigated using qRT-PCR and western blot assays. Additionally, we analyzed DC-SIGN and RP11-181G12.2 expression levels in GC specimens based on the Cancer Genome Atlas database.

Results: In this study, the results showed that DC-SIGN was highly expressed in GC cells and significantly correlated with advanced clinical stage and lymphatic metastasis. Downregulation of DC-SIGN significantly inhibited the proliferation, cell cycle progression, migration and invasion of GC cells in vitro. The reverse results could partly be seen with the upregulation of DC-SIGN. Mechanistically, knockdown of DC-SIGN inactivated the JAK2/STAT3 signaling pathway, and overexpression of DC-SIGN activated the JAK2/STAT3 signaling pathway. In addition, through LncPath microarray analysis, we identified a lncRNA, RP11-181G12.2, that was significantly upregulated after knockdown of DC-SIGN; this was also confirmed by qRT-PCR. Furthermore, RP11-181G12.2 knockdown enhanced DC-SIGN expression in GC cells, further activating the JAK2/STAT3 signaling pathway. In contrast, DC-SIGN overexpression suppressed RP11-181G12.2 expression.

Conclusions: Our study suggests that DC-SIGN might be involved in the progression of GC by regulating the JAK2/STAT3 signaling pathway and affecting lncRNA RP11-181G12.2 expression.

Keywords: DC-SIGN; Gastric cancer; JAK2/STAT3; lncRNA.

MeSH terms

  • Cell Adhesion Molecules / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Disease Progression
  • Down-Regulation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Janus Kinase 2 / genetics*
  • Lectins, C-Type / genetics*
  • RNA, Long Noncoding / genetics*
  • Receptors, Cell Surface / genetics*
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / genetics*
  • Stomach / pathology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Up-Regulation / genetics

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Lectins, C-Type
  • RNA, Long Noncoding
  • Receptors, Cell Surface
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • JAK2 protein, human
  • Janus Kinase 2