All-trans retinoic acid suppresses malignant characteristics of CD133-positive thyroid cancer stem cells and induces apoptosis

PLoS One. 2017 Aug 17;12(8):e0182835. doi: 10.1371/journal.pone.0182835. eCollection 2017.

Abstract

Recently, diagnoses of radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) have become more common; prognosis is poor. It has been suggested that cancer stem cells account for radiotherapy resistance. By flow cytometry, different expression percents of CD133 and OCT4 in thyroid cancer cell lines were detected. By real-time quantitative PCR, different mRNA expression of CD133, OCT4, GLUT1, thyroglobulin (TG), thyroperoxidase (TPO) and sodium iodine symporter (NIS) was analyzed; the localization of CD133, OCT4, and NIS expression was examined using immunofluorescence confocal microscopy. Different expression of CD133, OCT4, and NIS in 21 human thyroid cancer and nodule tissues was investigated using immunohistochemistry. CD133-positive cells were isolated by magnetic sorting. Stronger colony formation ability of CD133-positive and weaker ability of CD133-negative cells in vivo were examined by colony formation. The effects of all-trans retinoic acid (ATRA) on CD133-positive cells in vivo were explored with Cell Counting Kit-8, colony formation, apoptosis, cell cycle, and ethynyl deoxyuridine assays. The ARO cell line and RAI-R DTC tissue specimens had more CD133-positive cells. NIS expression was significantly lower in RAI-R DTC tissue compared to radioiodine-sensitive DTC (RAI-DTC) tissue and specimens from patients with thyroid nodule. ATRA inhibited the stem cell characteristics of CD133-positive cells and induced CD133-positive cell differentiation to CD133-negative cells, and promoted CD133-positive cell apoptosis.

MeSH terms

  • AC133 Antigen / genetics*
  • AC133 Antigen / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis*
  • Cell Line, Tumor
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Humans
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Thyroglobulin / genetics
  • Thyroglobulin / metabolism
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology*
  • Tretinoin / pharmacology*

Substances

  • AC133 Antigen
  • Antineoplastic Agents
  • Glucose Transporter Type 1
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Tretinoin
  • Thyroglobulin

Grants and funding

This work was supported by the Fundamental Research Funds of Shandong University-Clinical Research Funds of QiLu Hospital [grant number 2014QLKY20], the Research Fund of Affiliated Qilu Hospital of Shandong University [grant number 2015QLMS30] and the National Natural Science Foundation of China [grant number 81272181]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.