SOX2/SOX17 Molecular Switching by Polyphenols to Promote Thyroid Differentiation in 2D and 3D Models of Anaplastic

Fabiola Vaglica1, Mattia Biondo2, Giuseppe Siragusa2

  • 1Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (Promise), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, PA, Italy.

Biology
|December 30, 2025
PubMed

Insights

Resveratrol (RSV) and its analogs re-differentiate anaplastic thyroid cancer (ATC) cells by modulating SOX2/SOX17 balance. This polyphenol treatment offers a promising strategy to improve therapeutic responsiveness in ATC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cancer treatment resistance often stems from altered tumor cell gene profiles.
  • Reprogramming cancer cells toward a differentiated phenotype is a promising therapeutic strategy.

Purpose of the Study:

  • To investigate if resveratrol (RSV) and its analogs (3-MET-OX, ISOR-H-PG) can modulate the SOX2/SOX17 balance and promote re-differentiation in anaplastic thyroid cancer (ATC) cells.
  • To assess the effects of these polyphenols on gene expression and differentiation markers in ATC cells.

Main Methods:

  • Human ATC cell lines (SW1736, 8505c) and non-tumoral thyroid cells (Nthy-ori 3-1) were cultured in 2D and 3D systems.
  • Cells were treated with sub-cytotoxic doses of RSV, 3-MET-OX, and ISOR-H-PG.
  • Analyses included cell viability, cell cycle, spheroid morphology, and gene expression profiling.

Main Results:

  • Polyphenol treatment induced G1 arrest in 2D cultures, indicating a cytostatic effect.
  • In 3D cultures, polyphenols disrupted ATC spheroids and modulated gene expression.
  • RSV and 3-MET-OX reduced stemness markers (SOX2, NANOG) and increased differentiation markers (SOX17, TTF-1, TPO, NIS).

Conclusions:

  • Modulation of the SOX2/SOX17 ratio by RSV and its analogs provides a mechanistic basis for ATC cell re-differentiation.
  • This polyphenol-induced re-differentiation strategy holds potential for improving therapeutic responsiveness in anaplastic thyroid cancer.

Related Concept Videos

Synthesis and Regulation of Thyroid Hormones01:20

Synthesis and Regulation of Thyroid Hormones

Low blood levels of the thyroid hormones — triiodothyronine (T3) and thyroxine (T4) — signal the hypothalamus to release the thyrotropin-releasing hormone (TRH). TRH then reaches the pituitary gland and stimulates the release of thyroid-stimulating hormone(TSH) into the bloodstream.
Upon reaching the thyroid gland, TSH stimulates the follicular cells' active uptake of iodide ions from the blood. The ions diffuse to the apical surface of the cells and are oxidized to iodine. The...
7.0K
Methods of Nuclear Reprogramming01:24

Methods of Nuclear Reprogramming

Nuclear reprogramming is a process of transforming one cell type into an unrelated cell type by epigenetic changes that alter the cell’s original gene expression pattern. Such epigenetic changes force cells to express a different set of genes, which play a significant role in inducing transformation into other cell types. Nuclear reprogramming offers applications in reproductive cloning for livestock propagation and regenerative medicine — developing patient-specific cells for...
2.1K
Pleiotropy01:33

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
43.1K
Forced Transdifferentiation01:28

Forced Transdifferentiation

Transdifferentiation, also known as lineage reprogramming, was first discovered by Selman and Kafatos in 1974 in silkmoths. They observed that the moths’ cuticle-producing cells transformed into salt-producing cells. Many such cases of natural transdifferentiation occur in organisms. In humans, pancreatic alpha cells can become beta cells. In newts, the loss of the eye’s lens causes the pigmented epithelial cells to transdifferentiate into the lens cells.
Artificial...
2.3K