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

Abstract

Here we describe a conditional doxycycline-dependent mouse model of RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis. In these mice, after 10 days of doxycycline (dox) administration, RET/PTC3 expression induced mitogen activated protein kinase (MAPK) stimulation and a proliferative response which resulted in the formation of hyperplastic thyroid lesions. This was followed, after 2 months, by growth arrest accompanied by typical features of oncogene-induced senescence (OIS), including upregulation of p16INK4A and p21CIP, positivity at the Sudan black B, activation of the DNA damage response (DDR) markers γH2AX and pChk2 T68, and induction of p53 and p19ARF. After 5 months, about half of thyroid lesions escaped OIS and formed tumors that remained dependent on RET/PTC3 expression. This progression was accompanied by activation of AKT-FOXO1/3a pathway and increased serum TSH levels.

Expression and function of nuclear receptor coactivator 4 isoforms in transformed endometriotic and malignant ovarian cells

“…NCOA4 (represented by two well studied isoforms) is not only a recently identified molecule mediating regulation of intracellular iron content in a ferritinophagic pathway [ 28 , 29 ] but also as a player in modulating hormone functions as a nuclear co-activator [ 15 , 16 , 32 ]. Other reported functions for NCOA4 include (a) regulation of DNA replication to modulate DNA stability [ 52 ], (b) modulation of DNA damage response and cellular senescence [ 53 ], and (c) increasing cellular proliferation and migration/invasion of breast as well as prostate cancer cells [ 17 , 18 ]. Herein (as shown in Figure 7C ), we have defined that NCOA4 is elevated in transformed endometriotic cells (relative to non-transformed cells), in malignant ovarian cancer cells and in a subset of ovarian tumors.…”

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…RET gene fusions lead to kinase activation, in turn augmenting signal transduction along classical pathways such as the MAPK and the PI3K/AKT ones [4,5,80]. This causes gain of RET oncogenic activity, as shown for the most frequent fusions (CCDC6-RET, NCOA4-RET, KIF5B-RET) using cell-based assays as well as constitutive or conditional transgenic mouse models [28,29,50,51,[81][82][83][84]. Various mechanisms may contribute to fusion-mediated RET activation, including: (i) as mentioned above, the increased kinase expression, due to the replacement of the 5'-upstream RET promoter, that is normally active mainly in neuronal cell lineages, with that of the fusion partners [85], and (ii) the dimerization/oligomerization of the RET kinase domain mediated by protein-protein interaction motifs, typically coiled-coil domains, present in the fusion partners, that leads to ligand-independent kinase activation [65,86].…”

Oxidative stress in thyroid carcinomas: biological and clinical significance

“…Thyroid tumour-associated oncogenes (BRAF V600E , H-RAS V12 , RET/PTC1 and RET/PTC3) have been shown to trigger permanent cell cycle arrest, known as oncogeneinduced senescence (OIS), in human thyroid cells (Vizioli et al 2011, Weyemi et al 2012, Bellelli et al 2018. Severe or irreparable DNA damage is involved in the proliferative arrest and induces a DNA damage response that precedes senescence.…”