HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer
Abstract Hepatoma-derived growth factor (HDGF) expression is associated with poor prognosis in non-small cell lung cancer (NSCLC); however, whether HDGF affects gefitinib resistance in NSCLC remains unknown. This study aimed to explore the role of HDGF in gefitinib resistance in NSCLC and to discove...
Main Authors: | , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
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Nature Publishing Group
2023-06-01
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Series: | Cell Death Discovery |
Online Access: | https://doi.org/10.1038/s41420-023-01476-0 |
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author | Shuyan Han Zhihua Tian Huifang Tian Haibo Han Jun Zhao Yanna Jiao Chunli Wang Huifeng Hao Shan Wang Jialei Fu Dong Xue Hong Sun Pingping Li |
author_facet | Shuyan Han Zhihua Tian Huifang Tian Haibo Han Jun Zhao Yanna Jiao Chunli Wang Huifeng Hao Shan Wang Jialei Fu Dong Xue Hong Sun Pingping Li |
author_sort | Shuyan Han |
collection | DOAJ |
description | Abstract Hepatoma-derived growth factor (HDGF) expression is associated with poor prognosis in non-small cell lung cancer (NSCLC); however, whether HDGF affects gefitinib resistance in NSCLC remains unknown. This study aimed to explore the role of HDGF in gefitinib resistance in NSCLC and to discover the underlying mechanisms. Stable HDGF knockout or overexpression cell lines were generated to perform experiments in vitro and in vivo. HDGF concentrations were determined using an ELISA kit. HDGF overexpression exacerbated the malignant phenotype of NSCLC cells, while HDGF knockdown exerted the opposite effects. Furthermore, PC-9 cells, which were initially gefitinib-sensitive, became resistant to gefitinib treatment after HDGF overexpression, whereas HDGF knockdown enhanced gefitinib sensitivity in H1975 cells, which were initially gefitinib-resistant. Higher levels of HDGF in plasma or tumor tissue also indicated gefitinib resistance. The effects of HDGF on promoting the gefitinib resistance were largely attenuated by MK2206 (Akt inhibitor) or U0126 (ERK inhibitor). Mechanistically, gefitinib treatment provoked HDGF expression and activated the Akt and ERK pathways, which were independent of EGFR phosphorylation. In summary, HDGF contributes to gefitinib resistance by activating the Akt and ERK signaling pathways. The higher HDGF levels may predict poor efficacy for TKI treatment, thus it has the potential to serve as a new target for overcoming tyrosine kinase inhibitor resistance in combating NSCLC. |
first_indexed | 2024-03-13T06:13:39Z |
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id | doaj.art-81a48af684bd4b0f8c19d5c3af641103 |
institution | Directory Open Access Journal |
issn | 2058-7716 |
language | English |
last_indexed | 2024-03-13T06:13:39Z |
publishDate | 2023-06-01 |
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series | Cell Death Discovery |
spelling | doaj.art-81a48af684bd4b0f8c19d5c3af6411032023-06-11T11:05:57ZengNature Publishing GroupCell Death Discovery2058-77162023-06-019111210.1038/s41420-023-01476-0HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancerShuyan Han0Zhihua Tian1Huifang Tian2Haibo Han3Jun Zhao4Yanna Jiao5Chunli Wang6Huifeng Hao7Shan Wang8Jialei Fu9Dong Xue10Hong Sun11Pingping Li12Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteCentral Laboratory, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteCentral Laboratory, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteThe Tissue Bank, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteDepartment of Thoracic Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteDepartment of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteDepartment of Oncology, Infectious Disease Hospital of Heilongjiang ProvinceDepartment of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteDepartment of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteDepartment of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteDepartment of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteDepartment of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteDepartment of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & InstituteAbstract Hepatoma-derived growth factor (HDGF) expression is associated with poor prognosis in non-small cell lung cancer (NSCLC); however, whether HDGF affects gefitinib resistance in NSCLC remains unknown. This study aimed to explore the role of HDGF in gefitinib resistance in NSCLC and to discover the underlying mechanisms. Stable HDGF knockout or overexpression cell lines were generated to perform experiments in vitro and in vivo. HDGF concentrations were determined using an ELISA kit. HDGF overexpression exacerbated the malignant phenotype of NSCLC cells, while HDGF knockdown exerted the opposite effects. Furthermore, PC-9 cells, which were initially gefitinib-sensitive, became resistant to gefitinib treatment after HDGF overexpression, whereas HDGF knockdown enhanced gefitinib sensitivity in H1975 cells, which were initially gefitinib-resistant. Higher levels of HDGF in plasma or tumor tissue also indicated gefitinib resistance. The effects of HDGF on promoting the gefitinib resistance were largely attenuated by MK2206 (Akt inhibitor) or U0126 (ERK inhibitor). Mechanistically, gefitinib treatment provoked HDGF expression and activated the Akt and ERK pathways, which were independent of EGFR phosphorylation. In summary, HDGF contributes to gefitinib resistance by activating the Akt and ERK signaling pathways. The higher HDGF levels may predict poor efficacy for TKI treatment, thus it has the potential to serve as a new target for overcoming tyrosine kinase inhibitor resistance in combating NSCLC.https://doi.org/10.1038/s41420-023-01476-0 |
spellingShingle | Shuyan Han Zhihua Tian Huifang Tian Haibo Han Jun Zhao Yanna Jiao Chunli Wang Huifeng Hao Shan Wang Jialei Fu Dong Xue Hong Sun Pingping Li HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer Cell Death Discovery |
title | HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer |
title_full | HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer |
title_fullStr | HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer |
title_full_unstemmed | HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer |
title_short | HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer |
title_sort | hdgf promotes gefitinib resistance by activating the pi3k akt and mek erk signaling pathways in non small cell lung cancer |
url | https://doi.org/10.1038/s41420-023-01476-0 |
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