Abstract
Anaplastic thyroid carcinoma (ATC) is almost universally fatal. Elevated keratin-8 (KRT8) protein expression is an established diagnostic cancer biomarker in several epithelial cancers (but not ATC). Several keratins, including KRT8, have been suggested to have a role in cell biology beyond that of structural cytoskeletal proteins. Here, we provide evidence that KRT8 plays a direct role in the growth of ATCs. Genomic and transcriptomic analysis of >5000 patients demonstrates that KRT8 mutation and copy number amplification are frequently evident in epithelial-derived cancers. Carcinomas arising from diverse tissues exhibit KRT8 mRNA and protein overexpression when compared to normal tissue levels. Similarly, in a panel of patient-derived ATC cell lines and patient tumors, KRT8 expression shows a similar pattern. sh-RNA-mediated KRT8 knockdown in these cell lines increases apoptosis, whereas forced overexpression of KRT8 confers resistance to apoptosis under peroxide-induced cell stress conditions. We further show that KRT8 protein binds to annexin A2, a protein known to mediate apoptosis as well as the redox pathway.
Highlights
Most cases of thyroid cancer have >95% five-year survival rate, but patients with anaplastic thyroid carcinoma (ATC) have a median survival time of less than 6 months [1,2]
We provide evidence that KRT8 is significantly elevated in a subset of patients with various types types of cancers, including in ATC patient tumors and tumor-derived ATC patient-derived xenograft (PDX) cell lines
KRT8 expression is elevated in a subset of ATC tumors
Summary
Most cases of thyroid cancer have >95% five-year survival rate, but patients with anaplastic thyroid carcinoma (ATC) have a median survival time of less than 6 months [1,2]. While ATC is a rare disease (2% of all thyroid cancers), it represents 30–45% of thyroid cancer deaths [2,3]. Current treatment modalities fail to significantly prolong survival [2,3]; long-term survivors are so rare that they warrant case reports even on single individuals [4].
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