NF-κB signaling activation and roles in thyroid cancers: implication of MAP3K14/NIK

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling

Background:

• Follicular-derived thyroid cancers (TC) with aggressive behavior and treatment resistance have poor prognoses.
• Nuclear Factor-kappa B (NF-κB) signaling pathways are implicated in the progression of various cancers.

Purpose of the Study:

• To characterize NF-κB pathways in TC and identify novel therapeutic targets.
• To investigate the role of NF-κB in tumor progression, particularly in BRAF-mutated papillary thyroid carcinoma (PTC).

Main Methods:

• Immunoblot and gel shift assays to assess NF-κB pathway activation in TC cell lines.
• RNA sequencing analysis of TCGA papillary thyroid carcinoma cohort.
• Functional assays to evaluate the role of NF-κB components in cell migration and invasion.
• Analysis of NF-κB-inducing kinase (NIK) expression in PTC samples.

Main Results:

• Both classical and alternative NF-κB pathways are constitutively activated in TC cell lines, forming RelA/p50 and RelB/p50 dimers.
• A tumor progression-related NF-κB signature was identified in BRAF^V600E-mutated PTCs.
• RelA and RelB promote cell migration and invasion, controlling the expression of genes like MMP1, PLAU, LCN2, and LGALS3.
• NF-κB-inducing kinase (NIK) was identified as a novel contributor to constitutive NF-κB activation in TC cell lines and is overexpressed in PTC samples.

Conclusions:

• NF-κB pathways are activated in TC and play a significant role in tumor cell invasion, especially in BRAF^V600E-mutated PTC.
• NF-κB-inducing kinase (NIK) is implicated in TC invasiveness and represents a potential therapeutic target for advanced thyroid cancer.