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Updated: Jul 4, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Nuclear factor-kappaB activation is associated with somatic and germ line RET mutations in medullary thyroid
Pilar Gallel1, Judit Pallares, Xavier Dolcet
1Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, Institut de Recerca Biomedica de Lleida, 25198 Lleida, Spain.
Abstract:
The nuclear factor-kappaB (NF-kappaB) family of transcription factors regulates a wide variety of cellular processes including cell growth, differentiation, and apoptosis. NF-kappaB has been shown to be activated through several signaling pathways that involve growth factor receptors. The aim of the study was to assess the immunohistochemical expression of members of the NF-kappaB family and the putative targets of NF-kappaB in a series of medullary thyroid carcinomas (MTCs), in correlation with RET mutational status. A tissue microarray was constructed from paraffin-embedded blocks of 48 MTCs (13 familial, 35 sporadic) previously evaluated for germ line and somatic RET mutations. Immunohistochemical evaluation included members of the NF-kappaB (p50, p65, p52, c-Rel, RelB) family, as well as putative targets of NF-kappaB such as Flip, Bcl-xL, and cyclin D1. Nuclear immunostaining for members of NF-kappaB was frequent in MTCs (p50, 19%; p65, 68%; p52, 86.6%; c-Rel, 75%; RelB, 36%). MTCs with germ line or somatic RET mutations (29 cases) showed NF-kappaB nuclear translocation (particularly of p65, P = .035) more frequently than MTCs without RET mutations (19 cases). Immunostaining for putative targets of NF-kappaB showed a significant statistical association between p65 and Bcl-xL (P = .024). In addition, Bcl-xL expression was statistically higher in the tumors with exon 16 RET mutation in comparison with those with exon 10 and 11 RET mutations or wild-type RET (P = .002). Moreover, the significance of RETsignaling in NF-kappaB activation was evaluated in the RET-mutated TT cell line. TT cells were infected with lentiviruses carrying short hairpin RNA to knock down RET expression, and NF-kappaB activity was assessed by luciferase reporter assays. Silencing of RET in the TT cell line produced a significant decrease in NF-kappaB activation and reduction in ERK1/2. The results suggest that the NF-kappaB is frequently activated in MTCs. The results also support the hypothesis that RET activation by somatic or germ line mutations may be responsible for NF-kappaB activation in MTCs.
Insights
Nuclear factor-kappaB (NF-kappaB) is frequently activated in medullary thyroid carcinomas (MTCs). RET mutations correlate with NF-kappaB activation, suggesting a role for RET signaling in MTC pathogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Nuclear factor-kappaB (NF-kappaB) is a key transcription factor regulating cellular processes like growth and apoptosis.
- NF-kappaB activation is implicated in various cancers, often through growth factor receptor signaling pathways.
Purpose of the Study:
- To investigate the expression of NF-kappaB family members and their targets in medullary thyroid carcinomas (MTCs).
- To correlate NF-kappaB expression with RET mutational status in MTCs.
- To elucidate the role of RET signaling in NF-kappaB activation within MTCs.
Main Methods:
- Construction of a tissue microarray from 48 MTC samples (familial and sporadic).
- Immunohistochemical evaluation of NF-kappaB family members (p50, p65, p52, c-Rel, RelB) and targets (Flip, Bcl-xL, cyclin D1).
- Correlation analysis with RET mutational status (germ line and somatic).
- In vitro study using RET-mutated TT cell line with RET gene silencing via shRNA and NF-kappaB activity assessment via luciferase reporter assays.
Main Results:
- Frequent nuclear expression of NF-kappaB members was observed in MTCs, particularly p52 (86.6%) and c-Rel (75%).
- MTCs with RET mutations showed significantly higher NF-kappaB nuclear translocation, especially p65 (P = .035), compared to those without RET mutations.
- A significant association was found between p65 and Bcl-xL expression (P = .024).
- Bcl-xL expression was higher in MTCs with exon 16 RET mutations.
- Silencing RET in TT cells led to decreased NF-kappaB activation and ERK1/2 signaling.
Conclusions:
- NF-kappaB is frequently activated in medullary thyroid carcinomas.
- RET activation, through somatic or germ line mutations, likely contributes to NF-kappaB activation in MTCs.
- These findings highlight the potential therapeutic targeting of the RET-NF-kappaB pathway in MTCs.
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