MicroRNA-221-3p, a TWIST2 target, promotes cervical cancer metastasis by directly targeting THBS2

Cell Death Dis. 2017 Dec 14;8(12):3220. doi: 10.1038/s41419-017-0077-5.

Abstract

MicroRNAs have implicated in the relapse and metastasis of cervical cancer, which is the leading cause of cervical cancer-related mortality. However, the underlying molecular mechanisms need further elucidation. Our present study revealed that miR-221-3p is transcriptionally promoted in metastatic cervical cancer tissues compared with non-metastatic cervical cancer tissues. Forced overexpression of miR-221-3p facilitated EMT and promoted cell migration and invasion in vitro and lymphatic metastasis in vivo. Twist homolog 2 (TWIST2) was found to be a key transcription factor binding to the promoter of miR-221-3p. Inhibitors of miR-221-3p drastically reduced the induction of EMT and decreased cell migration and invasion mediated by TWIST2. By combined computational and experimental approaches, THBS2 was recognized to be an important downstream target gene of miR-221-3p. In cervical cancer tissues, especially with lymphatic metastasis, miR-221-3p and TWIST2 were increased and THBS2 was decreased, suggesting that TWIST2 induces miR-221-3p expression and consequently suppresses its direct target THBS2 in lymphatic metastasis CC. Our findings uncover a mechanistic role for miR-221-3p in lymph node metastasis, suggesting that miR-221-3p is upregulated by the transcription factor TWIST2 and downregulates its target THBS2, which may potentially promote lymph node metastasis in cervical cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antagomirs / genetics
  • Antagomirs / metabolism
  • Base Sequence
  • Binding Sites
  • Cell Movement
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • HeLa Cells
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Lymphatic Metastasis
  • Mice
  • Mice, Nude
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Thrombospondins / genetics*
  • Thrombospondins / metabolism
  • Twist-Related Protein 1 / genetics*
  • Twist-Related Protein 1 / metabolism
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / therapy
  • Xenograft Model Antitumor Assays

Substances

  • Antagomirs
  • Luminescent Proteins
  • MIRN221 microRNA, human
  • MicroRNAs
  • Repressor Proteins
  • TWIST2 protein, human
  • Thrombospondins
  • Twist-Related Protein 1
  • red fluorescent protein
  • thrombospondin 2