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Potential role of P2X7R in esophageal squamous cell carcinoma proliferation

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Abstract

Esophageal cancer is an aggressive tumor and is the sixth leading cause of cancer death worldwide. ATP is well known to regulate cancer progression in a variety of models by different mechanisms, including P2X7R activation. This study aimed to evaluate the role of P2X7R in esophageal squamous cell carcinoma (ESCC) proliferation. Our results show that treatment with high ATP concentrations induced a decrease in cell number, cell viability, number of polyclonal colonies, and reduced migration of ESCC. The treatment with the selective P2X7R antagonist A740003 or siRNA for P2X7 reverted this effect in the KYSE450 cell line. In addition, results showed that P2X7R is highly expressed, at mRNA and protein levels, in KYSE450 lineage. Additionally, KYSE450, KYSE30, and OE21 cells express P2X3R, P2X4R, P2X5R, P2X6R, and P2X7R genes. P2X1R is expressed by KYSE30 and KYSE450, and only KYSE450 expresses the P2X2R gene. Furthermore, esophageal cancer cell line KYSE450 presented higher expression of E-NTPDases 1 and 2 and of Ecto-5′-NT/CD73 when compared to normal cells. This cell line also exhibits ATPase, ADPase, and AMPase activity, although in different levels, and the co-treatment of apyrase was able to revert the antiproliferative effects of ATP. Moreover, results showed high immunostaining for P2X7R in biopsies of patients with esophageal carcinoma, indicating the involvement of this receptor in the growth of this type of cancer. The results suggest that P2X7R may be a potential pharmacological target to treat ESCC and can lead us to further investigate the effect of this receptor in cancer cell progression.

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Acknowledgements

This work was supported by CAPES and CNPq scholarships, PUCRS, and FINEP research grant “Implantação, Modernização e Qualificação de Estrutura de Pesquisa da PUCRS” (PUCRSINFRA) no. 01.11.0014-00. We would like to thank Dr. Guido Lenz from UFRGS for P2X7R antibody donation, Dr. Mohamed I Parker from ICGEB, Dr. Ana Maria O. Battastini from UFRGS, and Dr. Maria Martha Campos from PUCRS for their intellectual and technical advice.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    André A Santos Jr, Angélica R Cappellari, Marina P Gehring & Fernanda B Morrone

  2. Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    Fernanda O de Marchi & Fernanda B Morrone

  3. Programa de Pós-graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    Aline Zaparte, Vinicius D da Silva & Fernanda B Morrone

  4. Faculdade de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    Caroline A Brandão & Vinicius D da Silva

  5. Hospital São Lucas da PUCRS, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    Tiago Giuliani Lopes & Vinicius D da Silva

  6. Programa de Carcinogênese Molecular, Coordenação de Pesquisa, Instituto Nacional do Câncer (INCA), Rio de Janeiro, Brazil

    Luis Felipe Ribeiro Pinto

  7. Departamento de Bioquímica, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

    Luis Felipe Ribeiro Pinto

  8. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Luiz Eduardo Baggio Savio, Aline Cristina Abreu Moreira-Souza & Robson Coutinho-Silva

  9. International Centre for Genetic Engineering and Biotechnology (ICGEB), Cancer Genomics Group, Cape Town, South Africa

    Juliano D Paccez & Luiz F Zerbini

  10. Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa

    Luiz F Zerbini

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  1. André A Santos Jr
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Corresponding author

Correspondence to Fernanda B Morrone.

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Conflicts of interest

André A Santos Jr declares that he has no conflict of interest.

Angélica R Cappellari declares that she has no conflict of interest.

Fernanda O de Marchi declares that she has no conflict of interest.

Marina P Gehring declares that she has no conflict of interest.

Aline Zaparte declares that she has no conflict of interest.

Caroline A Brandão declares that she has no conflict of interest.

Tiago Giuliani Lopes declares that he has no conflict of interest.

Luis Felipe Ribeiro Pinto that he has no conflict of interest.

Vinicius Duval da Silva declares that he has no conflict of interest.

Robson Coutinho-Silva declares that he has no conflict of interest.

Juliano D Paccez declares that she has no conflict of interest.

Luiz F Zerbini declares that he has no conflict of interest.

Fernanda B Morrone declares that she has no conflict of interest.

Ethical approval

Histological samples of human ESCC and esophageal tissue samples of patients with esophagitis were collected, between July and December 2015, from patients who underwent endoscopic procedures with biopsies and/or surgical resection at Pontificia Universidade Católica do Rio Grande do Sul (PUCRS, Porto Alegre, Brazil). The diagnosis was reviewed by two certified pathologists with at least 20-year experience in surgical pathology. Samples were obtained in accordance with approved ethical standards of the Institutional Research Ethics Committee (CAAE 4969 6115.0.0000.5336).

Electronic supplementary material

Fig. S1

ATP reduces the cell migration in KYSE450 cancer cell line. (A) Representative images of ATP treatments at various times after monolayer wounding. (B) Quantification of cell migration assays. The means shown were obtained from 10 measurements of each time point and condition. The experiment was performed two times in triplicate. (TIFF 10159 kb)

High resolution image (GIF 264 kb)

Fig. S2

Evaluation of E-NTPDases and CD73 expression and activity in EPC2, KYSE30, and OE21 esophageal cancer cell line. (A) RT-qPCR analysis of NTPD1, NTPD2, and CD73 relative expression was performed and the values were showed as ΔCq relative expression in relation to GAPDH in EPC2, KYSE30, and OE21 cancer cell lines. The significance was described as **p < 0.01 and ***p < 0.001 and indicate difference in relation to EPC2 cell line and #p < 0.05 and ###p < 0.001 indicating difference of KYSE30. (B) Evaluation of enzymatic activity as described in “Material and Methods” section. *P < 0.05 and indicate difference in relation to ADP hydrolysis. (TIFF 7227 kb)

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Santos, A.A., Cappellari, A.R., de Marchi, F.O. et al. Potential role of P2X7R in esophageal squamous cell carcinoma proliferation. Purinergic Signalling 13, 279–292 (2017). https://doi.org/10.1007/s11302-017-9559-2

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