家族性非髄様甲状腺癌の感受性遺伝子としてのPAK4変異の同定
Familial non-medullary thyroid carcinoma (FNMTC) carries an inherited predisposition whose molecular basis remains incompletely understood. A five-member pedigree with papillary thyroid carcinoma was analyzed using whole-exome and Sanger sequencing, leading to identification of a PAK4 variant, c.T1250C (p.I417T), in affected individuals. Computational modeling indicated that this substitution disrupts hydrophobicity, intramolecular hydrogen bonding, and phosphorylation sites, thereby destabilizing the protein structure. Experimentally, the I417T mutant promoted nuclear translocation of phosphorylated PAK4 and conferred enhanced cell proliferation, invasiveness, accelerated division, and suppressed apoptosis relative to wild-type cells. In vivo lung metastasis models corroborated increased metastatic potential. Mechanistically, the mutant activates tumor necrosis factor signaling via PAK4-JNK-NF-κB-c-Jun phosphorylation cascades, distinct from the wild-type PAK4-NF-κB-MMP9 axis, and additionally interacts with MMP3 to regulate its promoter activity. These findings position PAK4 I417T as a candidate diagnostic molecular marker for FNMTC.
The I417T substitution in PAK4 enhances nuclear translocation of phosphorylated PAK4, activating TNF signaling through sequential phosphorylation of JNK, NF-κB, and c-Jun, while also binding MMP3 and upregulating its promoter activity, collectively driving tumor proliferation, invasion, and metastasis.
This is basic research at the cellular or molecular level. For human application, inhalation is the most promising delivery route, but inhalation carries explosion risk and concentration matters (empirical LFL of 10%; high-concentration devices are not recommended).
See also:
https://h2-papers.org/en/papers/38411500