Downregulation of NEAT1 reverses the radioactive iodine resistance of papillary thyroid carcinoma cell via miR-101-3p/FN1/PI3K-AKT signaling pathway

Cell Cycle. 2019 Jan;18(2):167-203. doi: 10.1080/15384101.2018.1560203. Epub 2018 Dec 30.

Abstract

Considering the resistance of papillary thyroid cancer (PTC) 131I therapy, this study was designed to find a solution at molecular respect. By probing into lncRNA-NEAT1/miR-101-3p/FN1 axis and PI3K/AKT signaling pathway, this study provided a potential target for PTC therapy. 131I-resistant cell lines were established by continuous treatment with median-lethal 131I. Bioinformatic analysis was applied to filtrate possible lncRNA/miRNA/mRNA and related signaling pathway. Luciferase reporter assay was employed in the verification of the targeting relationship between lncRNA and miRNA as well as miRNA and mRNA. MTT assay and flow cytometry assay were performed to observe the impact of NEAT1/miR-101-3p/FN1 on cell viability and apoptosis in radioactivity iodine (RAI)-resistant PTC cell lines, respectively. Western blot and qRT-PCR were conducted to measure the expression of proteins and mRNAs in RAI-resistant PTC tissues and cells. Meanwhile, endogenous PTC mice model were constructed, in order to verify the relation between NEAT1 and RAI-resistance in vivo. NEAT1 was over-expressed in RAI-resistant PTC tissues and cell lines and could resist RAI by accelerating proliferation accompanied by suppressing apoptosis. It indicated that overexpressed NEAT1 restrained the damage of RAI to tumor in both macroscopic and microcosmic. Besides, NEAT1/miR-101-3p exhibited a negative correlation by directly targeting each other. The expression of FN1, an overexpressed downstream protein in RAI-resistance PTC tissues, could be tuned down by miR-101-3p, while the decrease could be restored by NEAT1. In conclusion, both in vitro and in vivo, NEAT1 suppression could inhibit 131I resistance of PTC by upregulating miR-101-3p/FN1 expression and inactivated PI3K/AKT signaling pathway both in vitro and in vivo.

Keywords: FN1; NEAT1; PI3K/AKT signaling pathway; PTC; RAI-resistance; miR-101-3p.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Fibronectins / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Iodine Radioisotopes / pharmacology*
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • MicroRNAs / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Thyroid Cancer, Papillary / metabolism*
  • Thyroid Neoplasms / metabolism*
  • Transfection

Substances

  • FN1 protein, human
  • Fibronectins
  • Iodine Radioisotopes
  • MIRN101 microRNA, human
  • MIRN101 microRNA, mouse
  • MicroRNAs
  • NEAT1 long non-coding RNA, human
  • NEAT1 long non-coding RNA, mouse
  • RNA, Long Noncoding
  • Proto-Oncogene Proteins c-akt

Grants and funding

The study was supported by the National Natural Science Foundation, Regional Science Foundation Project [Grant Number: 81860312]; Applied Basic Research in Yunnan Province (Joint Special Project of Kunming Medical University) [Grant Number: 2017FE467(−080), 2018FE001(−062)]; and Yunnan Provincial Health and Family Planning Commission Medical Discipline Leaders Training Program [Grant Number: D-201649].