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Pathologic significance of AKT, mTOR, and GSK3β proteins in oral squamous cell carcinoma-affected patients

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Abstract

Phosphatidylinositol-3-kinases are kinases that lead to AKT phosphorylation and thus mTOR and GSK3β activation. These proteins are linked to tumorigenesis, but their roles in driving cervical lymph node (CLN) metastasis of oral squamous cell carcinoma (OSCC) cells are unknown. This study aimed to investigate the role of AKT, mTOR, and GSK3β proteins in the occurrence of CLN metastasis in OSCC patients. Ninety and 18 paraffin-embedded OSCC and oral mucosa samples were included, respectively. We divided our OSCC patients into non-metastasizing (PNM) and metastasizing (PM) groups, and the expression of total AKT, pAKT1Thr308, pAKTSer473, GSK3β, pGSK3βSer9, and pmTORSer2448 was analyzed by immunohistochemistry. The mean expression of GSK3β, pGSK3βSer9, total AKT, and pmTOR2448 was always higher in the OSCC tissues than that in the controls. A positive correlation was also found among these proteins. Total AKT, pmTORSer2448, and pGSK3βSer9 expression was significantly higher in the PNM and PM groups than that in the control group. However, only GSK3β expression was significantly higher in the PM group compared with the PNM group. High expression levels of GSK3β and pGSK3βSer9 were significantly associated with CLN metastasis, but only GSK3β remained an independent predictor of CLN metastasis. pGSK3βSer9 and CLN metastasis were associated with a poor prognosis, but only the latter remained an independent prognostic parameter. Kaplan-Meier survival curves showed that pGSK3βSer9 and CLN metastasis were significantly related to reduced survival rates. These results suggest that AKT and mTOR proteins are involved in OSCC biology and that GSK3β itself may drive CLN metastatic spread of OSCC cells.

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Acknowledgements

We are thankful to the Fundação de Amparo a Pesquisa do Estado de Minas Gerais (APQ-01746-13) e o Conselho Nacional de Desenvolvimento Científico e Tecnológico (471130/2013-13) for the financial support. I would like to thank the AC Camargo Cancer Hospital (São Paulo, Brazil) for providing the Tissue Microarray Core facility and Mr. Carlos Ferreira Nascimento for the technical support.

Funding sources

This study was supported by the Fundação de Amparo a Pesquisa do Estado de Minas Gerais (grant number APQ-01746-13) e o Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant number 471130/2013-13), Brazil.

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Authors and Affiliations

  1. Department of Cell and Molecular Biology and Pathogenic Bioagents, School of Medicine, University of São Paulo, 1900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil

    Flávia Sayuri Matsuo

  2. Department of Immunology, Institute of Biomedical Science, Federal University of Uberlândia, 1720 Pará Avenue, Block 4C, Uberlândia, Minas Gerais, 38400-902, Brazil

    Marília Ferreira Andrade & Marcelo José Barbosa Silva

  3. Department of Oral Pathology, School of Dentistry, Federal University of Uberlândia, 1720 Pará Avenue, Block 4L, Uberlândia, Minas Gerais, 38400-902, Brazil

    Adriano Mota Loyola & Sérgio Vitorino Cardoso

  4. Department of Surgery, School of Medicine, Federal University of Uberlândia, 1720 Pará Avenue, Uberlândia, Minas Gerais, 38400-902, Brazil

    Sindeval José da Silva

  5. Department of Morphology, Institute of Biomedical Science, Federal University of Uberlândia, 1720 Pará Avenue, Block 2B, Uberlândia, Minas Gerais, 38400-902, Brazil

    Paulo Rogério de Faria

  6. Instituto de Ciências Biomédicas, Laboratório de Histologia, Universidade Federal de Uberlândia, Avenida Amazonas S/N, Bloco 2B, Sala 2B-254, Uberlândia, Minas Gerais, 38405-320, Brazil

    Paulo Rogério de Faria

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  1. Flávia Sayuri Matsuo
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  2. Marília Ferreira Andrade
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  3. Adriano Mota Loyola
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  4. Sindeval José da Silva
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  5. Marcelo José Barbosa Silva
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  6. Sérgio Vitorino Cardoso
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Contributions

Flávia Sayuri Matsuo and Marilia Ferreira Andrade performed all experiments and wrote the manuscript; Adriano Mota Loyola did the histopathological review of all lesions and oral healthy mucosa, interpreted the immunohistochemical stainings, and revised the manuscript; Sindeval Jose Silva raised patients’ medical files and revised the manuscript; Marcelo José Barbosa Silva and Sérgio Vitorino Cardoso performed all statistical analyses, interpreted data, and revised the manuscript; Paulo Rogério de Faria contributed to the design and data analyses, and wrote the manuscript. All authors approved the final manuscript prior to its submission.

Corresponding author

Correspondence to Paulo Rogério de Faria.

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The authors declare that they have no conflict of interest.

Statement of ethical approval

This study was approved by the Committee on Research and Ethics of the Federal University of Uberlândia (CAAE number: 15188713.9.0000.5152).

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Matsuo, F.S., Andrade, M.F., Loyola, A.M. et al. Pathologic significance of AKT, mTOR, and GSK3β proteins in oral squamous cell carcinoma-affected patients. Virchows Arch 472, 983–997 (2018). https://doi.org/10.1007/s00428-018-2318-0

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