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Article Open Access

The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation

  • Authors:
    • Yeo-Jin Lee
    • Eunsun Jung
    • Jinhyeon Choi
    • Jin-Seong Hwang
    • Eun-Jeong Jeong
    • Yuna Roh
    • Hyun Seung Ban
    • Sunhong Kim
    • Seon-Kyu Kim
    • Seon-Young Kim
    • Jeong-Ki Min
    • Tae-Su Han
    • Jang-Seong Kim
  • View Affiliations / Copyright

    Affiliations: Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
    Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 13
    |
    Published online on: November 28, 2022
       https://doi.org/10.3892/ijo.2022.5461
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Abstract

Endothelin receptor A (EDNRA) has been reported to play various crucial physiological roles and has been shown to be associated with the pathology of several diseases, including colorectal cancer (CRC). However, the molecular mechanisms of EDNRA in the development of human CRC have not been fully elucidated to date. In this context, the present study was performed to investigate biological functions and novel downstream signaling pathways affected by EDNRA, during CRC progression. First, using public data repositories, it was observed that the EDRNA expression levels were markedly increased in CRC tissues, as compared to normal tissues. Patients with CRC with an increased EDNRA expression exhibited a significantly decreased survival rate in comparison with those with a lower EDNRA expression. Furthermore, a positive correlation between the levels of EDNRA and its ligand, EDN1, was found in CRC tissues. The ectopic expression of EDNRA or its ligand, EDN1, promoted, whereas the silencing of EDNRA or EDN1 decreased cell proliferation and migration in vitro. To elucidate the signaling pathways involved in the regulation of EDNRA expression in CRC cells, a phosphokinase array analysis was performed, and it was observed that the knockdown of EDNRA substantially suppressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in CRC cells. Of note, STAT3 silencing simultaneously decreased EDN1 and EDNRA expression, with the expression of EDN1 and/or EDNRA appearing to be directly regulated by binding STAT3 to their promoter region, according to chromatin immunoprecipitation and promoter assays, ultimately indicating a positive feedback loop in the expression of EDNRA and EDN1. It was also observed that treatment with an EDNRA antagonist (macitentan), alone or in combination with cisplatin, suppressed cell growth and migration ability, and induced cell apoptosis. Collectively, these data suggest a critical role of the EDN1/EDNRA signaling pathway in CRC progression. Thus, the pharmacological intervention of this signaling pathway may prove to be a potential therapeutic approach for patients with CRC.
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Copy and paste a formatted citation
Spandidos Publications style
Lee Y, Jung E, Choi J, Hwang J, Jeong E, Roh Y, Ban HS, Kim S, Kim S, Kim S, Kim S, et al: The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation. Int J Oncol 62: 13, 2023.
APA
Lee, Y., Jung, E., Choi, J., Hwang, J., Jeong, E., Roh, Y. ... Kim, J. (2023). The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation. International Journal of Oncology, 62, 13. https://doi.org/10.3892/ijo.2022.5461
MLA
Lee, Y., Jung, E., Choi, J., Hwang, J., Jeong, E., Roh, Y., Ban, H. S., Kim, S., Kim, S., Kim, S., Min, J., Han, T., Kim, J."The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation". International Journal of Oncology 62.1 (2023): 13.
Chicago
Lee, Y., Jung, E., Choi, J., Hwang, J., Jeong, E., Roh, Y., Ban, H. S., Kim, S., Kim, S., Kim, S., Min, J., Han, T., Kim, J."The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation". International Journal of Oncology 62, no. 1 (2023): 13. https://doi.org/10.3892/ijo.2022.5461
Copy and paste a formatted citation
x
Spandidos Publications style
Lee Y, Jung E, Choi J, Hwang J, Jeong E, Roh Y, Ban HS, Kim S, Kim S, Kim S, Kim S, et al: The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation. Int J Oncol 62: 13, 2023.
APA
Lee, Y., Jung, E., Choi, J., Hwang, J., Jeong, E., Roh, Y. ... Kim, J. (2023). The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation. International Journal of Oncology, 62, 13. https://doi.org/10.3892/ijo.2022.5461
MLA
Lee, Y., Jung, E., Choi, J., Hwang, J., Jeong, E., Roh, Y., Ban, H. S., Kim, S., Kim, S., Kim, S., Min, J., Han, T., Kim, J."The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation". International Journal of Oncology 62.1 (2023): 13.
Chicago
Lee, Y., Jung, E., Choi, J., Hwang, J., Jeong, E., Roh, Y., Ban, H. S., Kim, S., Kim, S., Kim, S., Min, J., Han, T., Kim, J."The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation". International Journal of Oncology 62, no. 1 (2023): 13. https://doi.org/10.3892/ijo.2022.5461
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