PLCγ1/PKCθ downstream signaling controls cutaneous T-cell lymphoma development and progression

García-Díaz, Nuria; Casar, Berta; Alonso Alonso, Ruth; Quevedo, Laura; Rodríguez, Marta; Ruso-Julve, Fulgencio; Esteve-Codina, Anna; Gut, Marta; Gru, Alejandro A.; González Vela, María del Carmen; Gut, Ivo Glynne; Rodriguez-Peralto, José Luis; Varela, Ignacio; Ortiz-Romero, Pablo L.; Piris, Miguel A.; Vaqué, José Pedro

PLCγ1/PKCθ downstream signaling controls cutaneous T-cell lymphoma development and progression

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dc.contributor.author García-Díaz, Nuria
dc.contributor.author Casar, Berta
dc.contributor.author Alonso Alonso, Ruth
dc.contributor.author Quevedo, Laura
dc.contributor.author Rodríguez, Marta
dc.contributor.author Ruso-Julve, Fulgencio
dc.contributor.author Esteve-Codina, Anna
dc.contributor.author Gut, Marta
dc.contributor.author Gru, Alejandro A.
dc.contributor.author González Vela, María del Carmen
dc.contributor.author Gut, Ivo Glynne
dc.contributor.author Rodriguez-Peralto, José Luis
dc.contributor.author Varela, Ignacio
dc.contributor.author Ortiz-Romero, Pablo L.
dc.contributor.author Piris, Miguel A.
dc.contributor.author Vaqué, José Pedro
dc.date.accessioned 2022-01-24T12:35:36Z
dc.date.available 2022-01-24T12:35:36Z
dc.date.issued 2022
dc.description.abstract Developing mechanistic rationales can improve the clinical management of cutaneous T-cell lymphomas. 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 signal transducer and activator of transcription 3 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 protein kinase C theta (PKCθ) inhibited signal transducer and activator of transcription 3 activation, impaired proliferation, and promoted apoptosis in cutaneous T-cell lymphoma cells. A PKCθ-dependent transcriptome in mycosis fungoides/Sézary syndrome cells revealed potential effector genes controlling cytokine signaling, TP53, and actin cytoskeleton dynamics. Consistently, an in vivo chicken embryo model xenografted with mycosis fungoides 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 mycosis fungoides cells significantly correlated with that of PRKCQ (PKCθ) in 81 human mycosis fungoides samples. In summary, PKCθ can play a central role in the activation of malignant cutaneous T-cell lymphoma mechanisms via multiple routes, including, but not restricted to, STAT3. These mechanisms may, in turn, serve as targets for specific therapies.
dc.description.sponsorship This work has been funded by the Instituto de Salud Carlos III (ISCIII)/FEDER (PI16/00156, PI19/00204, and ASOCIACION LUCHAMOS POR LA VIDA to JPV; PI17/0957 to PLOR). NGD has been supported by a predoctoral contract from UC-IDIVAL. BC holds a RyC contract from MICINN (RYC2018-024004). AEC is funded by ISCIII/MINECO/FEDER (PT17/0009/0019)
dc.format.mimetype application/pdf
dc.identifier.citation García-Díaz N, Casar B, Alonso-Alonso R, Quevedo L, Rodríguez M, Ruso-Julve F et al. PLCγ1/PKCθ downstream signaling controls cutaneous T-cell lymphoma development and progression. J Invest Dermatol. 2022;142(5):1391-400. DOI: 10.1016/j.jid.2021.09.024
dc.identifier.doi http://dx.doi.org/10.1016/j.jid.2021.09.024
dc.identifier.issn 0022-202X
dc.identifier.uri http://hdl.handle.net/10230/52300
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Journal of Investigative Dermatology. 2022;142(5):1391-400.
dc.rights © 2021 Nuria García-Díaz et al. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.other Genètica
dc.subject.other Limfomes
dc.subject.other Manifestacions cutànies de les malalties generals
dc.title PLCγ1/PKCθ downstream signaling controls cutaneous T-cell lymphoma development and progression
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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