miR-338 modulates proliferation and autophagy by PI3K/AKT/mTOR signaling pathway in cervical cancer

Biomed Pharmacother. 2018 Sep;105:633-644. doi: 10.1016/j.biopha.2018.06.024. Epub 2018 Jun 10.

Abstract

Cervical cancer (CC) is a malignant solid tumor, which is one of the main causes of morbidity and mortality in women. Given that autophagy is an important factor promoting tumor progression, we aim to investigate the functional role of miR-338 in autophagy and proliferation of cervical cancer. In our study, expression of miR-338 was validated by quantitative RT-PCR in 30 paired cervical cancer tissues and normal tissues. We performed MTT, colony formation and cell cycle assay to explore the effect of miR-338 on cell proliferation. The level of autophagy was evaluated by observing the expression of LC3 formation under fluorescence microscope and detected the LC3 expression by western blot. We used luciferase reporter assays to identify the target gene about miR-338. We not only found that the level of miR-338 is decreased in cervical cancer tissues and cells, but also negatively correlated with the protein level of ATF2. In turn, restoring the expression of miR-338 inhibited proliferation in Hela and SiHa cells. Further mechanistic study identified that ATF2 as a direct target of miR-338. Forced lowexpression of miR-338 directly led to increased the level of autophagy in cervical cancer cells, which was similar to the mTOR signaling inhibitor rapamycin. The western blot analysis show that inhibited miR-338 expression could decrease the p-mTOR and p-p70S6 expression. Thus, we infer that miR-338 decreases autophagy level in cervical cancer cells by activating mTOR signaling pathway. In summary, our study demonstrate that miR-338 could inhibites proliferation and autophagy by targeting ATF2 via mTOR signaling pathway on cervical cancer cells. These results suggest a potential application of miR-338 in cervical cancer as a novel mechanism of tumor therapeutic.

Keywords: ATF2; Autophagy; PI3K/AKT/mTOR signaling pathway; Proliferation; miR-338.

MeSH terms

  • Activating Transcription Factor 2 / metabolism
  • Autophagy / genetics*
  • Cell Proliferation / genetics*
  • Female
  • HeLa Cells
  • Humans
  • MicroRNAs / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / pathology

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • MIRN338 microRNA, human
  • MicroRNAs
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases