Thyroid carcinoma (TC) is the most common endocrine neoplasia, with its incidence increasing in the last 40 years worldwide. The determination of genetic and/or protein markers for thyroid carcinoma could increase diagnostic precision. Accumulated evidence shows that Protein kinase 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 that PKCs can mediate the proliferative effects of thyroid hormones (THs) through their membrane receptor, the integrin αvβ3, in several cancer types. We found that PKCα is overexpressed in TC cell lines, 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 αvβ3 receptor, through AKT and Erk activation. In databases of TC patients, higher PKCα expression was associated with lower overall survival. Further analyses showed a positive correlation between PKCα and genes from the MAPK and PI3K-Akt pathways. Finally, immunohistochemical analysis showed abnormal upregulation of PKCα in human thyroid tumors. Our findings establish a potential role for PKCα in the control of hormone-induced proliferation that can be explored as a therapeutic and/or diagnostic target for TC.

Abnormal JAK/STAT pathway activation is widespread in virtually all T cell lymphomas (TCL) subtypes. However, activating mutations are insufficient to drive leukemic cell proliferation, which also requires enhanced upstream signaling. We have described that thyroid hormones (THs) contribute to the malignant phenotype of TCL by inducing intracellular transcriptional programs through integrin αvβ3 activation. Here we evaluate the effect of THs on JAK/STAT pathway and its implications on TCL therapy. We found that THs induce the activation of STAT1, 3, and 5, including the upregulation of target genes and metalloprotease activity. Furthermore, we observed that the integrin αvβ3 inhibitor, cilengitide, not only reverts these effects but also enhances the anti-lymphoma activity to a greater extent than the JAK1/2 inhibitor, ruxolitinib, when combined with bexarotene, a synthetic rexinoid clinically used for cutaneous TCL treatment. Additionally, we explored the mechanisms of action of cilengitide and bexarotene combination using preclinical TCL in vivo models and proteomic analysis. We found that this combinatorial protocol significantly reduced tumor STATs phosphorylation, MMPs activity, and the number of metastatic foci by regulating proteins involved in cell proliferation, angiogenesis, metabolism, and immune response. Additionally, we observed that high integrin αvβ3 mRNA levels are enriched in pathways associated with lymphoma progression and reduce overall survival in TCL patient samples. Our findings support the therapeutic potential of targeting THs signaling through integrin αvβ3 inhibition in combination with bexarotene as a less toxic therapeutic strategy to mitigate aberrant JAK/STAT activation and limit lymphoma dissemination