Neurotensin receptor 1 signaling promotes pancreatic cancer progression
Pancreatic cancer is one of the cancers with the poorest prognosis, with a 5‐year survival rate of approximately 5–10%. Thus, it is urgent to identify molecular targets for the treatment of pancreatic cancer. Using serial transplantations in a mouse pancreatic orthotopic inoculation model, we previo...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-01-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12815 |
| _version_ | 1818364603679113216 |
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| author | Kei Takahashi Shogo Ehata Kensuke Miyauchi Yasuyuki Morishita Keiji Miyazawa Kohei Miyazono |
| author_facet | Kei Takahashi Shogo Ehata Kensuke Miyauchi Yasuyuki Morishita Keiji Miyazawa Kohei Miyazono |
| author_sort | Kei Takahashi |
| collection | DOAJ |
| description | Pancreatic cancer is one of the cancers with the poorest prognosis, with a 5‐year survival rate of approximately 5–10%. Thus, it is urgent to identify molecular targets for the treatment of pancreatic cancer. Using serial transplantations in a mouse pancreatic orthotopic inoculation model, we previously produced highly malignant pancreatic cancer sublines with increased tumor‐forming abilities in vivo. Here, we used these sublines to screen molecular targets for the treatment of pancreatic cancer. Among the genes with increased expression levels in the sublines, we focused on those encoding cell surface receptors that may be involved in the interactions between cancer cells and the tumor microenvironment. Based on our previous RNA‐sequence analysis, we found increased expression levels of neurotensin (NTS) receptor 1 (NTSR1) in highly malignant pancreatic cancer sublines. Furthermore, re‐analysis of clinical databases revealed that the expression level of NTSR1 was increased in advanced pancreatic cancer and that high NTSR1 levels were correlated with a poor prognosis. Overexpression of NTSR1 in human pancreatic cancer cells Panc‐1 and SUIT‐2 accelerated their tumorigenic and metastatic abilities in vivo. In addition, RNA‐sequence analysis showed that MAPK and NF‐κB signaling pathways were activated upon NTS stimulation in highly malignant cancer sublines and also revealed many new target genes for NTS in pancreatic cancer cells. NTS stimulation increased the expression of MMP‐9 and other pro‐inflammatory cytokines and chemokines in pancreatic cancer cells. Moreover, the treatment with SR48692, a selective NTSR1 antagonist, suppressed the activation of the MAPK and NF‐κB signaling pathways and induction of target genes in pancreatic cancer cells in vitro, while the administration of SR48692 attenuated the tumorigenicity of pancreatic cancer cells in vivo. These findings suggest that NTSR1 may be a prognostic marker and a molecular target for pancreatic cancer treatment. |
| first_indexed | 2024-12-13T22:07:00Z |
| format | Article |
| id | doaj.art-091676d157b44a0986c15194fcfdf41a |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-13T22:07:00Z |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-091676d157b44a0986c15194fcfdf41a2022-12-21T23:29:49ZengWileyMolecular Oncology1574-78911878-02612021-01-0115115116610.1002/1878-0261.12815Neurotensin receptor 1 signaling promotes pancreatic cancer progressionKei Takahashi0Shogo Ehata1Kensuke Miyauchi2Yasuyuki Morishita3Keiji Miyazawa4Kohei Miyazono5Department of Molecular Pathology Graduate School of Medicine The University of Tokyo Bunkyo‐ku JapanDepartment of Molecular Pathology Graduate School of Medicine The University of Tokyo Bunkyo‐ku JapanDepartment of Molecular Pathology Graduate School of Medicine The University of Tokyo Bunkyo‐ku JapanDepartment of Molecular Pathology Graduate School of Medicine The University of Tokyo Bunkyo‐ku JapanDepartment of Biochemistry Graduate School of Medicine University of Yamanashi Chuo JapanDepartment of Molecular Pathology Graduate School of Medicine The University of Tokyo Bunkyo‐ku JapanPancreatic cancer is one of the cancers with the poorest prognosis, with a 5‐year survival rate of approximately 5–10%. Thus, it is urgent to identify molecular targets for the treatment of pancreatic cancer. Using serial transplantations in a mouse pancreatic orthotopic inoculation model, we previously produced highly malignant pancreatic cancer sublines with increased tumor‐forming abilities in vivo. Here, we used these sublines to screen molecular targets for the treatment of pancreatic cancer. Among the genes with increased expression levels in the sublines, we focused on those encoding cell surface receptors that may be involved in the interactions between cancer cells and the tumor microenvironment. Based on our previous RNA‐sequence analysis, we found increased expression levels of neurotensin (NTS) receptor 1 (NTSR1) in highly malignant pancreatic cancer sublines. Furthermore, re‐analysis of clinical databases revealed that the expression level of NTSR1 was increased in advanced pancreatic cancer and that high NTSR1 levels were correlated with a poor prognosis. Overexpression of NTSR1 in human pancreatic cancer cells Panc‐1 and SUIT‐2 accelerated their tumorigenic and metastatic abilities in vivo. In addition, RNA‐sequence analysis showed that MAPK and NF‐κB signaling pathways were activated upon NTS stimulation in highly malignant cancer sublines and also revealed many new target genes for NTS in pancreatic cancer cells. NTS stimulation increased the expression of MMP‐9 and other pro‐inflammatory cytokines and chemokines in pancreatic cancer cells. Moreover, the treatment with SR48692, a selective NTSR1 antagonist, suppressed the activation of the MAPK and NF‐κB signaling pathways and induction of target genes in pancreatic cancer cells in vitro, while the administration of SR48692 attenuated the tumorigenicity of pancreatic cancer cells in vivo. These findings suggest that NTSR1 may be a prognostic marker and a molecular target for pancreatic cancer treatment.https://doi.org/10.1002/1878-0261.12815neurotensinNTSR1orthotopic inoculation modelpancreatic cancerSR48692 |
| spellingShingle | Kei Takahashi Shogo Ehata Kensuke Miyauchi Yasuyuki Morishita Keiji Miyazawa Kohei Miyazono Neurotensin receptor 1 signaling promotes pancreatic cancer progression Molecular Oncology neurotensin NTSR1 orthotopic inoculation model pancreatic cancer SR48692 |
| title | Neurotensin receptor 1 signaling promotes pancreatic cancer progression |
| title_full | Neurotensin receptor 1 signaling promotes pancreatic cancer progression |
| title_fullStr | Neurotensin receptor 1 signaling promotes pancreatic cancer progression |
| title_full_unstemmed | Neurotensin receptor 1 signaling promotes pancreatic cancer progression |
| title_short | Neurotensin receptor 1 signaling promotes pancreatic cancer progression |
| title_sort | neurotensin receptor 1 signaling promotes pancreatic cancer progression |
| topic | neurotensin NTSR1 orthotopic inoculation model pancreatic cancer SR48692 |
| url | https://doi.org/10.1002/1878-0261.12815 |
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