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lncRNA DIRC3 regulates invasiveness and insulin-like growth factor signaling in thyroid cancer cells

Piotr T Wysocki1,2, Karol Czubak1, Anna A Marusiak3

  • 1Laboratory of Experimental Medicine, Medical University of Warsaw, Warsaw, Poland.

Endocrine-Related Cancer
|May 2, 2023
PubMed

Insights

The long non-coding RNA DIRC3 is downregulated in differentiated thyroid cancers (DTCs). Its reduced expression promotes cancer cell growth and invasiveness by affecting the IGF1/Akt signaling pathway.

Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • Differentiated thyroid cancers (DTCs) exhibit significant heritability, with germline variants linked to risk found in the poorly characterized long non-coding RNA gene, DIRC3.
  • The precise function of DIRC3 in thyroid cancer development and progression remains largely unknown.

Purpose of the Study:

  • To investigate the functional role of DIRC3 in differentiated thyroid cancers (DTCs).
  • To elucidate the molecular mechanisms by which DIRC3 influences thyroid cancer cell behavior and signaling pathways.

Main Methods:

  • Analysis of DIRC3 expression in patient-matched thyroid tissue and The Cancer Genome Atlas (TCGA) data.
  • In vitro studies involving silencing DIRC3 in thyroid cancer cell lines (MDA-T32, MDA-T120).
  • Transcriptomic profiling, gene rescue experiments, and assessment of cell phenotypes (migration, invasion, apoptosis, MTT reduction rate).
  • Investigation of the interaction between DIRC3, IGFBP5, IGF1, and the Akt signaling pathway.

Main Results:

  • DIRC3 is significantly downregulated in DTCs, and its higher expression correlates with reduced cancer recurrence risk.
  • DIRC3 knockdown in thyroid cancer cells increased migration and invasion, reduced apoptosis, and altered metabolic activity.
  • DIRC3 regulates the IGFBP5/IGF1/Akt axis, with reduced DIRC3 enhancing sensitivity to IGF1 stimulation and promoting Akt signaling.

Conclusions:

  • DIRC3 expression significantly impacts thyroid cancer cell phenotype and is a key regulator of the IGFBP5/IGF1/Akt signaling pathway.
  • The interplay between DIRC3 and IGF signaling pathways is implicated in the promotion of thyroid carcinogenesis.
  • DIRC3 may represent a potential therapeutic target or biomarker in differentiated thyroid cancers.
Keywords:
DIRC3IGF1IGFBP5invasivenessthyroid cancer

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