Developing mechanistic rationales can improve the clinical management of cutaneous T-cell lymphomas (CTCL). There is considerable genetic and biological evidence of a malignant network of signaling mechanisms, highly influenced by deregulated TCR/PLCγ1 activity, controlling the biology of these lesions. In addition, activated STAT3 is associated with clinical progression, although the alterations responsible for this have not been fully elucidated. Here we studied PLCγ1-dependent mechanisms that can mediate STAT3 activation and control tumor growth and progression. Downstream of PLCγ1, the pharmacological inhibition and genetic knockdown of PKCθ inhibited STAT3 activation, impaired proliferation, and promoted apoptosis in CTCL cells. A PKCθ-dependent transcriptome in MF/SS cells revealed potential effector genes controlling cytokine signaling, TP53, and actin cytoskeleton dynamics. Consistently, an in vivo chicken embryo model xenografted with MF cells showed that PKCθ blockage abrogates tumor growth and spread to distant organs. Finally, the expression of a number of PKCθ target genes, found in MF cells, significantly correlated with that of PRKCQ (PKCθ) in 81 human MF samples. In summary, PKCθ can play a central role in the activation of malignant CTCL mechanisms via multiple routes, including, but not restricted to, STAT3. These mechanisms may, in turn, serve as targets for specific therapies.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
PLCγ1/PKCθ Downstream Signaling Controls Cutaneous T-Cell Lymphoma Development And Progression.
