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TSH signaling overcomes B-RafV600E-induced senescence in papillary thyroid carcinogenesis through regulation of DUSP6

Young Hwa Kim1, Yong Won Choi1, Jae Ho Han2

  • 1Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, South Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, South Korea.

Neoplasia (New York, N.Y.)
|December 16, 2014
PubMed

Insights

Thyroid-stimulating hormone (TSH) signaling overcomes oncogene-induced senescence (OIS) in papillary thyroid carcinoma (PTC) by stabilizing dual specific phosphatase 6 (DUSP6). This process is crucial for B-RafV600E-driven PTC development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • The B-RafV600E mutation is common in papillary thyroid carcinoma (PTC) and initiates tumors, but also induces oncogene-induced senescence (OIS) in thyrocytes.
  • Understanding how PTC overcomes OIS is critical for explaining tumor development despite senescence induction.

Purpose of the Study:

  • To investigate the factors enabling PTC to overcome B-RafV600E-induced oncogene-induced senescence (OIS).
  • To elucidate the role of thyroid-stimulating hormone (TSH) and dual specific phosphatase 6 (DUSP6) in B-RafV600E-driven papillary thyroid carcinoma (PTC) progression.

Main Methods:

  • Analysis of p-extracellular signal-regulated kinases 1/2 (ERK1/2) and dual specific phosphatase 6 (DUSP6) expression in PTC with B-RafV600E mutation.
  • In vitro experiments assessing the effects of DUSP6 overexpression on B-RafV600E-induced senescence.
  • Investigating the interaction between reactive oxygen species (ROS), TSH, and DUSP6 stability.
  • Examining TSH receptor expression and downstream signaling pathways including Ras/AKT/glycogen synthase kinase 3β (GSK3β) and c-Myc.

Main Results:

  • Down-regulation of p-ERK1/2 and up-regulation of DUSP6 were observed in B-RafV600E-mutated PTC.
  • DUSP6 overexpression inhibited B-RafV600E-induced senescence in thyrocytes.
  • TSH stabilized DUSP6 protein by increasing Mn superoxide dismutase, counteracting ROS-mediated degradation and inhibiting senescence.
  • TSH signaling, alongside DUSP6, reactivated Ras signaling, activating Ras/AKT/GSK3β and stabilizing c-Myc, thereby promoting B-RafV600E-induced papillary thyroid carcinogenesis.

Conclusions:

  • Increased TSH signaling is essential for overcoming oncogene-induced senescence (OIS) in the context of B-RafV600E mutations.
  • The TSH-DUSP6 interaction plays a key role in reactivating pro-carcinogenic signaling pathways and promoting papillary thyroid carcinoma (PTC) development.
  • TSH signaling overcomes OIS and is vital for B-RafV600E-induced papillary thyroid carcinogenesis.

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