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Isozyme-specific abnormalities of PKC in thyroid cancer: evidence for post-transcriptional changes in PKC epsilon
Jeffrey A Knauf1, Laura S Ward, Yuri E Nikiforov
1Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Abstract:
PKC isozymes are the major binding proteins for tumor-promoting phorbol esters, and PKC activity is abnormal in a number of different human cancers. Less is known about putative structural and functional changes of specific PKC isozymes in human neoplasms. A single-point mutation of PKCalpha at position 881 of the coding sequence has been observed in human pituitary adenomas and up to 50% of thyroid follicular neoplasms, and a rearrangement of PKCepsilon was reported in a thyroid follicular carcinoma cell line, suggesting that these signaling proteins may play a role in thyroid tumorigenesis. To explore this possibility, we examined thyroid neoplasms for mutations and changes in expression levels of PKCepsilon or alpha. None of the 57 follicular adenomas, 26 papillary carcinomas (PCs), 7 follicular carcinomas, or the anaplastic carcinoma harbored the PKCalpha 881A>G mutation. Moreover, none of 15 PCs, 10 follicular adenomas, or 6 follicular carcinomas showed evidence of mutations of PKCepsilon. However, 8 of 11 PCs had major isozyme-specific reductions of the PKCepsilon protein, which occurred through either translational or posttranslational mechanisms. These data indicate that post-transcriptional changes in PKCepsilon are highly prevalent in thyroid tumors and may play a significant role in their development.
Insights
Protein kinase C (PKC) epsilon protein levels are significantly reduced in most thyroid tumors, suggesting post-transcriptional changes in PKCepsilon play a role in thyroid tumorigenesis.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Protein kinase C (PKC) isozymes are crucial signaling proteins implicated in various human cancers.
- Abnormal PKC activity and specific isozyme alterations are observed in neoplasms, but their role in thyroid tumorigenesis is not fully understood.
- Previous studies noted PKCalpha mutations in pituitary and thyroid tumors and PKCepsilon rearrangement in a thyroid cancer cell line.
Purpose of the Study:
- To investigate the potential role of PKCalpha and PKCepsilon in thyroid tumorigenesis.
- To examine thyroid neoplasms for mutations and altered expression levels of PKCalpha and PKCepsilon.
Main Methods:
- Analysis of 57 follicular adenomas, 26 papillary carcinomas (PCs), 7 follicular carcinomas, and 1 anaplastic carcinoma for PKCalpha 881A>G mutation.
- Screening of 15 PCs, 10 follicular adenomas, and 6 follicular carcinomas for PKCepsilon mutations.
- Assessment of PKCepsilon protein expression levels in thyroid tumors.
Main Results:
- No PKCalpha 881A>G mutations were detected in any of the analyzed thyroid neoplasms.
- No mutations in PKCepsilon were found in the examined follicular adenomas, PCs, or follicular carcinomas.
- A significant reduction in PKCepsilon protein levels was observed in 8 out of 11 PCs, indicating post-transcriptional regulation.
Conclusions:
- Mutations in PKCalpha and PKCepsilon are not common drivers in the studied thyroid tumors.
- Post-transcriptional alterations, specifically reduced PKCepsilon protein levels, are highly prevalent in papillary thyroid carcinomas.
- These findings suggest that changes in PKCepsilon expression play a significant role in the development of thyroid tumors.