HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer
Background: The treatment of non-small-cell lung cancer (NSCLC) involves platinum-based chemotherapy. It is typically accompanied by chemoresistance resulting from antioxidant properties conferred by cancer stem cells (CSCs). Human epidermal growth factor receptor 2 (HER2) enhances CSCs and antioxid...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1663 |
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| author | Kuang-Tai Kuo Cheng-Hsin Lin Chun-Hua Wang Narpati Wesa Pikatan Vijesh Kumar Yadav Iat-Hang Fong Chi-Tai Yeh Wei-Hwa Lee Wen-Chien Huang |
| author_facet | Kuang-Tai Kuo Cheng-Hsin Lin Chun-Hua Wang Narpati Wesa Pikatan Vijesh Kumar Yadav Iat-Hang Fong Chi-Tai Yeh Wei-Hwa Lee Wen-Chien Huang |
| author_sort | Kuang-Tai Kuo |
| collection | DOAJ |
| description | Background: The treatment of non-small-cell lung cancer (NSCLC) involves platinum-based chemotherapy. It is typically accompanied by chemoresistance resulting from antioxidant properties conferred by cancer stem cells (CSCs). Human epidermal growth factor receptor 2 (HER2) enhances CSCs and antioxidant properties in cancers, including NSCLC. Methods: Here, we elucidated the role of histamine N-methyltransferase (HNMT), a histamine metabolism enzyme significantly upregulated in NSCLC and coexpressed with HER2. HNMT expression in lung cancer tissues was determined using quantitative reverse transcription PCR (RT-qPCR). A publicly available dataset was used to determine HNMT’s potential as an NSCLC target molecule. Immunohistochemistry and coimmunoprecipitation were used to determine HNMT–HER2 correlations and interactions, respectively. HNMT shRNA and overexpression plasmids were used to explore HNMT functions in vitro and in vivo. We also examined miRNAs that may target HNMT and investigated HNMT/HER2’s role on NSCLC cells’ antioxidant properties. Finally, how HNMT loss affects NSCLC cells’ sensitivity to cisplatin was investigated. Results: HNMT was significantly upregulated in human NSCLC tissues, conferred a worse prognosis, and was coexpressed with HER2. HNMT depletion and overexpression respectively decreased and increased cell proliferation, colony formation, tumorsphere formation, and CSCs marker expression. Coimmunoprecipitation analysis indicated that HNMT directly interacts with HER2. TARGETSCAN analysis revealed that HNMT is a miR-223 and miR-3065-5p target. TBHp treatment increased HER2 expression, whereas shHNMT disrupted the Nuclear factor erythroid 2-related factor 2 (Nrf2)/ hemeoxygenase-1 (HO-1)/HER2 axis and increased reactive oxygen species accumulation in NSCLC cells. Finally, shHNMT sensitized H441 cells to cisplatin treatment in vitro and in vivo. Conclusions: Therefore, HNMT upregulation in NSCLC cells may upregulate HER2 expression, increasing tumorigenicity and chemoresistance through CSCs maintenance and antioxidant properties. This newly discovered regulatory axis may aid in retarding NSCLC progression and chemoresistance. |
| first_indexed | 2024-03-09T23:46:09Z |
| format | Article |
| id | doaj.art-ceff45ee7ff340db8a56154db01e708a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:46:09Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ceff45ee7ff340db8a56154db01e708a2023-11-23T16:44:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233166310.3390/ijms23031663HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung CancerKuang-Tai Kuo0Cheng-Hsin Lin1Chun-Hua Wang2Narpati Wesa Pikatan3Vijesh Kumar Yadav4Iat-Hang Fong5Chi-Tai Yeh6Wei-Hwa Lee7Wen-Chien Huang8Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanTaipei Heart Institute, Taipei Medical University, Taipei 110, TaiwanDepartment of Dermatology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, TaiwanDivision of Urology, Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta 55281, IndonesiaDepartment of Medical Research & Education, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, TaiwanDepartment of Medical Research & Education, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, TaiwanDepartment of Medical Research & Education, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, TaiwanDepartment of Pathology, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, TaiwanDepartment of Medicine, MacKay Medical College, New Taipei City 252, TaiwanBackground: The treatment of non-small-cell lung cancer (NSCLC) involves platinum-based chemotherapy. It is typically accompanied by chemoresistance resulting from antioxidant properties conferred by cancer stem cells (CSCs). Human epidermal growth factor receptor 2 (HER2) enhances CSCs and antioxidant properties in cancers, including NSCLC. Methods: Here, we elucidated the role of histamine N-methyltransferase (HNMT), a histamine metabolism enzyme significantly upregulated in NSCLC and coexpressed with HER2. HNMT expression in lung cancer tissues was determined using quantitative reverse transcription PCR (RT-qPCR). A publicly available dataset was used to determine HNMT’s potential as an NSCLC target molecule. Immunohistochemistry and coimmunoprecipitation were used to determine HNMT–HER2 correlations and interactions, respectively. HNMT shRNA and overexpression plasmids were used to explore HNMT functions in vitro and in vivo. We also examined miRNAs that may target HNMT and investigated HNMT/HER2’s role on NSCLC cells’ antioxidant properties. Finally, how HNMT loss affects NSCLC cells’ sensitivity to cisplatin was investigated. Results: HNMT was significantly upregulated in human NSCLC tissues, conferred a worse prognosis, and was coexpressed with HER2. HNMT depletion and overexpression respectively decreased and increased cell proliferation, colony formation, tumorsphere formation, and CSCs marker expression. Coimmunoprecipitation analysis indicated that HNMT directly interacts with HER2. TARGETSCAN analysis revealed that HNMT is a miR-223 and miR-3065-5p target. TBHp treatment increased HER2 expression, whereas shHNMT disrupted the Nuclear factor erythroid 2-related factor 2 (Nrf2)/ hemeoxygenase-1 (HO-1)/HER2 axis and increased reactive oxygen species accumulation in NSCLC cells. Finally, shHNMT sensitized H441 cells to cisplatin treatment in vitro and in vivo. Conclusions: Therefore, HNMT upregulation in NSCLC cells may upregulate HER2 expression, increasing tumorigenicity and chemoresistance through CSCs maintenance and antioxidant properties. This newly discovered regulatory axis may aid in retarding NSCLC progression and chemoresistance.https://www.mdpi.com/1422-0067/23/3/1663non-small-cell lung cancercancer stem cellshuman epidermal growth factor receptor 2NRF2/HO-1/HER2 axisHNMT/HER2’s role |
| spellingShingle | Kuang-Tai Kuo Cheng-Hsin Lin Chun-Hua Wang Narpati Wesa Pikatan Vijesh Kumar Yadav Iat-Hang Fong Chi-Tai Yeh Wei-Hwa Lee Wen-Chien Huang HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer International Journal of Molecular Sciences non-small-cell lung cancer cancer stem cells human epidermal growth factor receptor 2 NRF2/HO-1/HER2 axis HNMT/HER2’s role |
| title | HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer |
| title_full | HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer |
| title_fullStr | HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer |
| title_full_unstemmed | HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer |
| title_short | HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer |
| title_sort | hnmt upregulation induces cancer stem cell formation and confers protection against oxidative stress through interaction with her2 in non small cell lung cancer |
| topic | non-small-cell lung cancer cancer stem cells human epidermal growth factor receptor 2 NRF2/HO-1/HER2 axis HNMT/HER2’s role |
| url | https://www.mdpi.com/1422-0067/23/3/1663 |
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