Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor

Kazuya Iwamoto, Hidekazu Takahashi, Daisuke Okuzaki, Hideo Osawa, Takayuki Ogino, Norikatsu Miyoshi, Mamoru Uemura, Chu Matsuda, Hirofumi Yamamoto, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki, Hidetoshi Eguchi

Research output: Contribution to journalArticle

Abstract

Background: The protein syntenin-1 is expressed by a variety of cell types, and is upregulated in various malignancies, including melanoma, breast cancer and glioma. Although the mechanism by which elevated syntenin-1 expression contributes to cancer has been described, the exact pathway has not been elucidated. Methods: To investigate the involvement of syntenin-1 in colorectal cancer (CRC), we performed immunohistochemical analysis of 139 CRC surgical specimens. We also examined syntenin-1 knockdown in CRC cell lines. Results: High syntenin-1 expression was associated with less differentiated histologic grade and poor prognosis, and was an independent prognostic indicator in CRC. Syntenin-1 knockdown in CRC cells reduced the presence of cancer stem cells (CSCs), oxaliplatin chemoresistance and migration. DNA microarray analysis and quantitative real-time polymerase chain reaction showed decreased prostaglandin E2 receptor 2 (PTGER2) expression in syntenin-1-knockdown cells. PTGER2 knockdown in CRC cells yielded the same phenotype as syntenin-1 knockdown. Celecoxib, which has anti-inflammatory effects by targeting cyclooxygenase-2, reduced CSCs and decreased chemoresistance, while prostaglandin E2 (PGE2) had the opposite effect. Conclusions: Our findings suggested that syntenin-1 enhanced CSC expansion, oxaliplatin chemoresistance and migration capability through regulation of PTGER2 expression. Syntenin-1 may be a promising new prognostic factor and target for anti-cancer therapies.

Original languageEnglish
JournalBritish journal of cancer
DOIs
Publication statusAccepted/In press - 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Iwamoto, K., Takahashi, H., Okuzaki, D., Osawa, H., Ogino, T., Miyoshi, N., Uemura, M., Matsuda, C., Yamamoto, H., Mizushima, T., Mori, M., Doki, Y., & Eguchi, H. (Accepted/In press). Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor. British journal of cancer. https://doi.org/10.1038/s41416-020-0965-9