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Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia

Roberto Bellelli1, Donata Vitagliano2, Giorgia Federico1

  • 1Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita' Federico II c/o Istituto di Endocrinologia e Oncologia Sperimentale, CNR, Via S Pansini 5, 80131 Naples, Italy.

Molecular and Cellular Endocrinology
|June 28, 2017
PubMed

Insights

A new mouse model reveals how RET/PTC3 oncogene drives thyroid tumors. Initially causing hyperplasia, the oncogene triggers senescence, but some lesions eventually escape to form tumors dependent on RET/PTC3 expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Thyroid tumors are a significant health concern.
  • The role of RET/PTC rearrangements in thyroid tumorigenesis is well-established.
  • Understanding the precise mechanisms of oncogene-induced thyroid tumor development is crucial for therapeutic strategies.

Purpose of the Study:

  • To develop and characterize a conditional doxycycline-dependent mouse model for studying RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis.
  • To investigate the temporal progression of thyroid lesions from hyperplasia to senescence and eventual tumor formation.
  • To elucidate the molecular pathways involved in oncogene-induced thyroid cancer.

Main Methods:

  • Generation of a conditional doxycycline-dependent mouse model expressing RET/PTC3.
  • Administration of doxycycline to induce oncogene expression.
  • Histopathological analysis of thyroid lesions at various time points (10 days, 2 months, 5 months).
  • Molecular analysis including Western blotting and assessment of senescence markers (p16INK4A, p21CIP), DNA damage response (DDR) markers (γH2AX, pChk2 T68), and signaling pathways (MAPK, AKT-FOXO1/3a).
  • Measurement of serum Thyroid-Stimulating Hormone (TSH) levels.

Main Results:

  • Doxycycline administration rapidly induced RET/PTC3 expression, leading to MAPK stimulation and thyroid hyperplasia within 10 days.
  • After 2 months, lesions exhibited oncogene-induced senescence (OIS) characterized by p16INK4A, p21CIP, Sudan black B positivity, DDR activation (γH2AX, pChk2 T68), and induction of p53 and p19ARF.
  • Approximately 50% of thyroid lesions escaped OIS after 5 months, forming tumors dependent on RET/PTC3 expression, associated with AKT-FOXO1/3a pathway activation and elevated serum TSH levels.

Conclusions:

  • The RET/PTC3 oncogene can induce thyroid hyperplasia, followed by a period of oncogene-induced senescence.
  • Tumorigenesis can occur through the escape of thyroid lesions from senescence, maintaining dependence on the oncogene.
  • This model provides a valuable tool for studying thyroid cancer progression and identifying potential therapeutic targets, highlighting the role of the AKT-FOXO1/3a pathway and TSH in tumor maintenance.
Keywords:
AKTOncogene-induced senescenceRET oncogeneThyroid cancer

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