A novel regulatory loop miR-101/ANXA2/EGR1 mediates malignant characteristics of liver cancer stem cells

Carcinogenesis. 2021 Feb 11;42(1):93-104. doi: 10.1093/carcin/bgaa055.

Abstract

Increasing evidence suggests that liver cancer stem cells (LCSCs) are the cellular determinants that promote tumor recurrence and metastases. Aberrantly expressed miRNAs were identified in LCSCs and found to play a significant role in modulating biological characteristics of LCSCs. In this study, we implemented miRNA microarrays in CD133+ LCSCs and found miR-101 expression was downregulated. Increasing miR-101 expression repressed the metastasis and tumorigenic potential in LCSCs. Further investigations showed that ANXA2 was a novel target of miR-101. And we revealed that ANXA2 plays a critical role in acceleration of cell cycle and enhancing the migration and invasion abilities of LCSCs. Elevated ANXA2 increased activation of extracellular signal-regulated kinase (ERK) which regulated SOX2 and cell cycle-related kinases. Moreover, ERK phosphorylation inhibited the expression of early growth response 1 (EGR1) which in turn restrained the transcription of miR-101. In vivo experiments, overexpression of miR-101 produced potent inhibitory effects on the growth of LCSCs xenograft tumors as well as ANXA2 knockdown. Taken together, our findings suggest a novel regulatory loop miR-101/ANXA2/EGR1 in LCSCs and may serve as potential therapeutic targets in liver cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A2 / genetics*
  • Annexin A2 / metabolism
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Computational Biology
  • Down-Regulation
  • Early Growth Response Protein 1 / genetics*
  • Early Growth Response Protein 1 / metabolism
  • Feedback, Physiological
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • MAP Kinase Signaling System / genetics
  • Male
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness / genetics
  • Neoplastic Stem Cells / pathology*
  • Phosphorylation / genetics
  • RNA-Seq
  • Xenograft Model Antitumor Assays

Substances

  • ANXA2 protein, human
  • Annexin A2
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • MIRN101 microRNA, human
  • MicroRNAs