PKCα Activation via the Thyroid Hormone Membrane Receptor Is Key to Thyroid Cancer Growth

Abstract

Thyroid carcinoma (TC) is the most common endocrine neoplasia, with its incidenceincreasing in the last 40 years worldwide. The determination of genetic and/or protein markers forthyroid carcinoma could increase diagnostic precision. Accumulated evidence shows that Proteinkinase C alpha (PKCα) contributes to tumorigenesis and therapy resistance in cancer. However,the role of PKCα in TC remains poorly studied. Our group and others have demonstrated thatPKCs can mediate the proliferative effects of thyroid hormones (THs) through their membranereceptor, the integrin αvβ3, in several cancer types. We found that PKCα is overexpressed in TC celllines, and it also appeared as the predominant expressed isoform in public databases of TC patients.PKCα-depleted cells significantly reduced THs-induced proliferation, mediated by the integrin αvβ3receptor, through AKT and Erk activation. In databases of TC patients, higher PKCα expressionwas associated with lower overall survival. Further analyses showed a positive correlation betweenPKCα and genes from the MAPK and PI3K-Akt pathways. Finally, immunohistochemical analysisshowed abnormal upregulation of PKCα in human thyroid tumors. Our findings establish a potentialrole for PKCα in the control of hormone-induced proliferation that can be explored as a therapeuticand/or diagnostic target for TC.