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

• Published in: British journal of cancer Vol. 123; no. 6; pp. 955 - 964
• Main Authors: Iwamoto, Kazuya, Takahashi, Hidekazu, Okuzaki, Daisuke, Osawa, Hideo, Ogino, Takayuki, Miyoshi, Norikatsu, Uemura, Mamoru, Matsuda, Chu, Yamamoto, Hirofumi, Mizushima, Tsunekazu, Mori, Masaki, Doki, Yuichiro, Eguchi, Hidetoshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.09.2020; Nature Publishing Group
• Subjects: 631/250/256/2515; 631/67/1504/1885; 631/67/1857; 631/67/71; Aged; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Celecoxib; Cell Line, Tumor; Cell Movement; Chemoresistance; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Cyclooxygenase-2; DNA microarrays; Drug Resistance; Drug Resistance, Neoplasm; Epidemiology; Female; Glioma; HEK293 Cells; Humans; Inflammation; Male; Melanoma; Middle Aged; Molecular Medicine; Neoplastic Stem Cells - pathology; Oncology; Oxaliplatin; Oxaliplatin - pharmacology; Phenotypes; Polymerase chain reaction; Prognosis; Prostaglandin E2; Receptors, Prostaglandin E - physiology; Stem cells; Syntenins - physiology
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0965-9

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.