Identification of P21 (CDKN1A) Activated Kinase 4 as a Susceptibility Gene for Familial Non-Medullary Thyroid Carcinoma
Authors' conclusion
Our study identified PAK4: c.T1250C: p.I417T as a potential susceptibility gene for FNMTC. The study concludes that the mutant form of PAK4 exhibits oncogenic function
Study context
- Population
- Five-member family affected by papillary thyroid carcinoma; other familial non-medullary thyroid carcinoma (FNMTC) patients and sporadic non-medullary thyroid carcinoma patientsfive-member family
- Comparison
- PAK4 mutant vs PAK4 wild-type cell lines
Methodological detailswhole-exome sequencing, Sanger sequencing, in silico prediction, in vitro cell phenotype experiments, in vivo lung distant metastasis models, transcriptome sequencing
- Whole-exome sequencing
- Sanger sequencing
- In silico prediction
- In vitro cell phenotype experiments
- In vivo lung distant metastasis models
- Transcriptome sequencing
Main finding
As reported in the abstract
- Mutation alters protein structure, potentially increasing instability by affecting hydrophobicity, intra-molecular hydrogen bonding and phosphorylation sites
- Mutation specifically promotes phosphorylated PAK4 nuclear translocation and expression in thyroid tissue and cell lines
- PAK4 I417T vs wild-type (WT): enhanced proliferation, invasiveness, accelerated cell division and inhibition of cell apoptosis in vitro
- PAK4 I417T: significant propensity for metastasis in vivo
- Mutant (MUT) activates tumor necrosis factor signaling via increased phosphorylation of PAK4, JNK, NFκB and c-Jun; WT activates it via the PAK4-NFκ-MMP9 axis
- PAK4 MUT protein interacts with MMP3 and regulates MMP3 promoter activity, not observed in WT
Original publication
Identification of P21 (CDKN1A) Activated Kinase 4 as a Susceptibility Gene for Familial Non-Medullary Thyroid Carcinoma. Thyroid. Published 25 March 2024. doi:10.
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