Oncotarget

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Esophageal squamous cell carcinoma transcriptome reveals the effect of FOXM1 on patient outcome through novel PIK3R3 mediated activation of PI3K signaling pathway

Pedro Nicolau-Neto _, Nathalia Meireles Da Costa, Paulo Thiago de Souza Santos, Isabela Martins Gonzaga, Maria Aparecida Ferreira, Simone Guaraldi, Miguel Angelo Moreira, Hector N. Seuánez, Lilian Brewer, Anke Bergmann, Mariana Boroni, Andre Luiz Mencalha, Cleber Dario Pinto Kruel, Sheila Coelho Soares Lima, Dominic Esposito, Tatiana Almeida Simão4 and Luis Felipe Ribeiro Pinto

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Oncotarget. 2018; 9:16634-16647. https://doi.org/10.18632/oncotarget.24621

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Abstract

Pedro Nicolau-Neto1, Nathalia Meireles Da Costa1, Paulo Thiago de Souza Santos1, Isabela Martins Gonzaga1, Maria Aparecida Ferreira2, Simone Guaraldi2, Miguel Angelo Moreira3, Hector N. Seuánez3, Lilian Brewer4, Anke Bergmann1, Mariana Boroni3, Andre Luiz Mencalha5, Cleber Dario Pinto Kruel6, Sheila Coelho Soares Lima1, Dominic Esposito7, Tatiana Almeida Simão4 and Luis Felipe Ribeiro Pinto1,4

1Molecular Carcinogenesis Program, Instituto Nacional de Câncer (INCA), Rio de Janeiro, 20231-050 RJ, Brasil

2Endoscopy Section, Instituto Nacional de Câncer (INCA), Praça Cruz Vermelha, 20230-130 RJ, Brasil

3Genetic Program, Instituto Nacional de Câncer (INCA), Rio de Janeiro, 20231-050 RJ, Brasil

4Biochemistry Department, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 20551-030 RJ, Brasil

5Biophysics and Biometry Department, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 20551-030 RJ, Brasil

6Surgery Department, Faculty of Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90035-003 RS, Brasil

7Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, 21701 MD, USA

Correspondence to:

Luis Felipe Ribeiro Pinto, email: lfrpinto@inca.gov.br

Keywords: esophageal squamous cell carcinoma; FOXM1; PIK3R3; PI3K/AKT pathway; target therapy

Received: August 15, 2017    Accepted: February 22, 2018    Published: March 30, 2018

ABSTRACT

Esophageal squamous cell carcinoma (ESCC) presents poor prognosis, and patients diagnosed with this tumor currently lack target treatments. Therefore, in order to identify potential targets for ESCC treatment, we carried out a transcriptome analysis with ESCC and paired nonmalignant surrounding mucosa samples, followed by a master regulator analysis, and further explored the role of the identified central regulatory genes through in vivo and in vitro assays. Among the transcription factors deregulated/enriched in ESCC, we focused on FOXM1 because of its involvement in the regulation of critical biological processes. A new transcriptome analysis performed with ESCC cell lineage TE-1 showed that the modulation of FOXM1 expression resulted in PIK3R3 expression changes, whereas chromatin immunoprecipitation assay revealed that FOXM1 was capable of binding onto PIK3R3 promoter, thus demonstrating that PIK3R3 is a new FOXM1 target. Furthermore, FOXM1 overexpression resulted in the activation of PIK3/AKT signaling pathway through PIK3R3-mediated AKT phosphorylation. Finally, the analysis of the clinic-pathological data of ESCC patients revealed that overexpression of both FOXM1 and PIK3R3 was associated with poor prognosis, but only the latter was an independent prognosis factor for ESCC patients. In conclusion, our results show that FOXM1 seems to play a central role in ESCC carcinogenesis by upregulating many oncogenes found overexpressed in this tumor. Furthermore, PIK3R3 is a novel FOXM1 target that triggers the activation of the PI3K/AKT pathway in ESCC cells.


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