MicroRNA-216b targets HK2 to potentiate autophagy and apoptosis of breast cancer cells via the mTOR signaling pathway

Int J Biol Sci. 2021 Jul 13;17(11):2970-2983. doi: 10.7150/ijbs.48933. eCollection 2021.

Abstract

Patients suffering from breast cancer (BC) still have a poor response to treatments, even though early detection and improved therapy have contributed to a reduced mortality. Recent studies have been inspired on the association between microRNAs (miRs) and therapies of BC. The current study set out to investigate the role of miR-216b in BC, and further analyze the underlining mechanism. Firstly, hexokinase 2 (HK2) and miR-216b were characterized in BC tissues and cells by RT-qPCR and Western blot assay. In addition, the interaction between HK2 and miR-216b was analyzed using dual luciferase reporter assay. BC cells were further transfected with a series of miR-126b mimic or inhibitor, or siRNA targeting HK2, so as to analyze the regulatory mechanism of miR-216b, HK2 and mammalian target of rapamycin (mTOR) signaling pathway, and to further explore their regulation in BC cellular behaviors. The results demonstrated that HK2 was highly expressed and miR-216b was poorly expressed in BC cells and tissues. HK2 was also verified as a target of miR-216b with online databases and dual luciferase reporter assay. Functionally, miR-216b was found to be closely associated with BC progression via inactivating mTOR signaling pathway by targeting HK2. Moreover, cell viability, migration and invasion were reduced as a result of miR-216b upregulation or HK2 silencing, while autophagy, cell cycle arrest and apoptosis were induced. Taken together, our findings indicated that miR-216 down-regulates HK2 to inactivate the mTOR signaling pathway, thus inhibiting the progression of BC. Hence, this study highlighted a novel target for BC treatment.

Keywords: Autophagy; Breast cancer; HK2; MicroRNA-216b; mTOR signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Autophagy / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hexokinase / genetics*
  • Humans
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • MIRN216 microRNA, human
  • MicroRNAs
  • HK2 protein, human
  • Hexokinase
  • MTOR protein, human
  • TOR Serine-Threonine Kinases