Modulação da expressão de proteínas reguladoras da morfologia mitocondrial altera as capacidades de invasão/migração das células tumorais

Um grupo de investigadores do Ipatimup e do Venetian Institute of Molecular Medicine, Pádua, Itália descobriu que, a desregulação da expressão das proteínas que controlam a morfologia e a dinâmica das mitocôndrias altera as capacidades de invasão e de migração das células tumorais. Os investigadores concluíram que as alterações da morfologia mitocondrial têm um papel importante no potencial de malignidade das células tumorais. 

As conclusões foram tiradas a partir do estudo de uma série de tumores humanos da tiroide, do banco de tecidos e tumores do Hospital de São João do Porto, e de linhas de células derivadas de tumores humanos, e foi publicado na revista Plos One em Março de 2015. Os investigadores verificaram que a modulação da expressão da proteína DRP1 (Dynamin-related protein 1), envolvida na divisão das mitocôndrias, alterar as capacidades de invasão e migração das células tumorais.   

Este estudo identifica possíveis novos alvos terapêuticos para tumores metastáticos.

Autores e Afiliações:

André Ferreira-da-Silva^1,2, Cristina Valacca³, Elisabete Rios^1,2,4, Helena Pópulo¹, Paula Soares^1,2, Manuel Sobrinho-Simões^1,2,4, Luca Scorrano^5,6,7, Valdemar Máximo^1,2‡ & Silvia Campello^3,7‡

¹Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal,

²Department of Pathology, Medical Faculty of University of Porto, Porto, Portugal,

³Department of Biology, University of Rome Tor Vergata, Rome, Italy,

⁴Department of Pathology, Hospital S. João, Porto, Portugal,

⁵Department of Biology, University of Padua, Padua, Italy,

⁶Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy,

⁷IRCCS Fondazione Santa Lucia, Rome, Italy

^‡VM and SC are joint senior authors on this work.

Abstract:

Oncocytic cell tumors are characterized by the accumulation of morphologically abnormal mitochondria in their cells, suggesting a role for abnormal mitochondrial biogenesis in oncocytic cell transformation. Little is known about the reason for the dysmorphology of accumulated mitochondria. The proteins regulating the morphology of mitochondria, the "mitochondria-shaping" proteins, can modulate their size and number; however, nothing is known hitherto about a possible involvement of mitochondrial dynamics in oncocytic cell transformation in tumors.

Our aim was to assess the status of the mitochondria morphology and its role in oncocytic cell transformation. We therefore evaluated the expression pattern of the main mitochondrial fusion and fission proteins in a series of thyroid cell tumor samples, as well as in thyroid tumor cell lines, with and without oncocytic cell features. The expression of mitochondrial fusion (Opa1,Mfn1 andMfn2) and fission (Drp1 and Fis1) proteins were evaluated by immunohistochemistry (IHC) in a series of 88 human thyroid tumors. In vitro studies, for comparative purposes and to deepen the study, were performed using TPC1 - a papillary thyroid carcinoma derived cell line—and XTC.UC1, an oncocytic follicular thyroid carcinoma-derived cell line.

Both IHC and in vitro protein analyses showed an overall increase in the levels of "mitochondrial- shaping" proteins in oncocytic thyroid tumors. Furthermore, overexpression of the pro-fission protein Drp1 was found to be associated with malignant oncocytic thyroid tumors. Interestingly, genetic and pharmacological blockage of Drp1 activity was able to influence thyroid cancer cells’ migration/invasion ability, a feature of tumor malignancy.

In this study we show that unbalanced mitochondrial dynamics characterize the malignant features of thyroid oncocytic cell tumors, and participate in the acquisition of the migrating phenotype.

Revista: Plos One

Link: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122308