Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer
ABSTRACT Purpose Small cell lung cancer (SCLC) is a highly aggressive disease associated with poor patient survival rates. The addition of an anti‐programmed death ligand 1 antibody to platinum combination chemotherapy can improve its prognosis. However, only a few patients achieve a long‐term respo...
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| Format: | Article |
| Language: | English |
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Wiley
2025-07-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.71034 |
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| author | Shotaro Ito Jun Sakakibara‐Konishi Mineyoshi Sato Tetsuaki Shoji Megumi Furuta Hirofumi Takahashi Kosuke Tsuji Daisuke Morinaga Masahiro Kashima Hidenori Kitai Junko Kikuchi Eiki Kikuchi Kanako C. Hatanaka Yutaka Hatanaka Kyoko Hida Takuro Noguchi Satoshi Konno |
| author_facet | Shotaro Ito Jun Sakakibara‐Konishi Mineyoshi Sato Tetsuaki Shoji Megumi Furuta Hirofumi Takahashi Kosuke Tsuji Daisuke Morinaga Masahiro Kashima Hidenori Kitai Junko Kikuchi Eiki Kikuchi Kanako C. Hatanaka Yutaka Hatanaka Kyoko Hida Takuro Noguchi Satoshi Konno |
| author_sort | Shotaro Ito |
| collection | DOAJ |
| description | ABSTRACT Purpose Small cell lung cancer (SCLC) is a highly aggressive disease associated with poor patient survival rates. The addition of an anti‐programmed death ligand 1 antibody to platinum combination chemotherapy can improve its prognosis. However, only a few patients achieve a long‐term response; thus, establishing new therapies for SCLC is crucial. Midkine (MDK) is a heparin‐binding growth factor involved in various biological processes, including cell proliferation and chemotherapeutic resistance, in diverse cancers. MDK has garnered attention as a therapeutic and diagnostic target for several cancers; however, only a few studies have evaluated its expression and function in SCLC. This study aimed to evaluate the MDK expression in human SCLC tissue and human SCLC cell lines, and to clarify its function in tumorigenesis. Methods MDK expression was analyzed in vitro and in vivo through ELISA, immunohistochemistry, and western blotting. Its effects on cell proliferation, as well as the effects of cisplatin, were evaluated using the MTT assay. Results MDK was pathologically expressed in human SCLC tumor tissues but not in normal lung tissues. Serum MDK concentrations in patients with SCLC reflected the SCLC tumor burden and were correlated with response to treatment. Moreover, MDK induced cell proliferation and attenuated the effects of cisplatin in SCLC cell lines. An MDK inhibitor and cisplatin exerted synergistic antitumor effects both in vitro and in vivo. Furthermore, MDK positively regulated the AKT pathway. Conclusion Our findings indicate that MDK promotes cell proliferation and chemotherapeutic resistance by activating the AKT pathway in SCLC cells. Therefore, MDK may be a potential therapeutic and diagnostic target for SCLC. |
| format | Article |
| id | doaj-art-809bce76d0dd474bbd81c161f3157de5 |
| institution | DOAJ |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-809bce76d0dd474bbd81c161f3157de52025-08-20T02:54:53ZengWileyCancer Medicine2045-76342025-07-011413n/an/a10.1002/cam4.71034Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung CancerShotaro Ito0Jun Sakakibara‐Konishi1Mineyoshi Sato2Tetsuaki Shoji3Megumi Furuta4Hirofumi Takahashi5Kosuke Tsuji6Daisuke Morinaga7Masahiro Kashima8Hidenori Kitai9Junko Kikuchi10Eiki Kikuchi11Kanako C. Hatanaka12Yutaka Hatanaka13Kyoko Hida14Takuro Noguchi15Satoshi Konno16Department of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanCenter for Development of Advanced Diagnostics Hokkaido University Hospital Sapporo JapanCenter for Development of Advanced Diagnostics Hokkaido University Hospital Sapporo JapanDepartment of Vascular Biology and Molecular Pathology Hokkaido University Faculty of Dental Medicine Sapporo JapanDepartment of Medical Oncology Faculty of Medicine and Graduate School of Medicine, Hokkaido University Sapporo JapanDepartment of Respiratory Medicine Faculty of Medicine, Hokkaido University Sapporo JapanABSTRACT Purpose Small cell lung cancer (SCLC) is a highly aggressive disease associated with poor patient survival rates. The addition of an anti‐programmed death ligand 1 antibody to platinum combination chemotherapy can improve its prognosis. However, only a few patients achieve a long‐term response; thus, establishing new therapies for SCLC is crucial. Midkine (MDK) is a heparin‐binding growth factor involved in various biological processes, including cell proliferation and chemotherapeutic resistance, in diverse cancers. MDK has garnered attention as a therapeutic and diagnostic target for several cancers; however, only a few studies have evaluated its expression and function in SCLC. This study aimed to evaluate the MDK expression in human SCLC tissue and human SCLC cell lines, and to clarify its function in tumorigenesis. Methods MDK expression was analyzed in vitro and in vivo through ELISA, immunohistochemistry, and western blotting. Its effects on cell proliferation, as well as the effects of cisplatin, were evaluated using the MTT assay. Results MDK was pathologically expressed in human SCLC tumor tissues but not in normal lung tissues. Serum MDK concentrations in patients with SCLC reflected the SCLC tumor burden and were correlated with response to treatment. Moreover, MDK induced cell proliferation and attenuated the effects of cisplatin in SCLC cell lines. An MDK inhibitor and cisplatin exerted synergistic antitumor effects both in vitro and in vivo. Furthermore, MDK positively regulated the AKT pathway. Conclusion Our findings indicate that MDK promotes cell proliferation and chemotherapeutic resistance by activating the AKT pathway in SCLC cells. Therefore, MDK may be a potential therapeutic and diagnostic target for SCLC.https://doi.org/10.1002/cam4.71034AKTbiomarkerMidkinesmall cell lung cancertherapeutic targettumor progression |
| spellingShingle | Shotaro Ito Jun Sakakibara‐Konishi Mineyoshi Sato Tetsuaki Shoji Megumi Furuta Hirofumi Takahashi Kosuke Tsuji Daisuke Morinaga Masahiro Kashima Hidenori Kitai Junko Kikuchi Eiki Kikuchi Kanako C. Hatanaka Yutaka Hatanaka Kyoko Hida Takuro Noguchi Satoshi Konno Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer Cancer Medicine AKT biomarker Midkine small cell lung cancer therapeutic target tumor progression |
| title | Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer |
| title_full | Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer |
| title_fullStr | Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer |
| title_full_unstemmed | Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer |
| title_short | Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer |
| title_sort | midkine promotes tumor growth and attenuates the effect of cisplatin in small cell lung cancer |
| topic | AKT biomarker Midkine small cell lung cancer therapeutic target tumor progression |
| url | https://doi.org/10.1002/cam4.71034 |
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