FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma
Abstract Background Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired dr...
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BMC
2025-02-01
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| Series: | Cancer & Metabolism |
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| Online Access: | https://doi.org/10.1186/s40170-025-00377-3 |
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| author | Tung-Wei Hsu Wan-Yu Wang Hsin-An Chen Tzu-Hsuan Wang Chih-Ming Su Po-Hsiang Liao Alvin Chen Kuei-Yen Tsai George Kokotos Cheng-Chin Kuo Ching-Feng Chiu Yen-Hao Su |
| author_facet | Tung-Wei Hsu Wan-Yu Wang Hsin-An Chen Tzu-Hsuan Wang Chih-Ming Su Po-Hsiang Liao Alvin Chen Kuei-Yen Tsai George Kokotos Cheng-Chin Kuo Ching-Feng Chiu Yen-Hao Su |
| author_sort | Tung-Wei Hsu |
| collection | DOAJ |
| description | Abstract Background Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC. Methods We investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine–resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine–resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259. Results We observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3’untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer. Conclusion Our results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy. |
| format | Article |
| id | doaj-art-e90834b85d624c83af4da9bf7e89ba1c |
| institution | DOAJ |
| issn | 2049-3002 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | Cancer & Metabolism |
| spelling | doaj-art-e90834b85d624c83af4da9bf7e89ba1c2025-08-20T02:48:33ZengBMCCancer & Metabolism2049-30022025-02-0113111910.1186/s40170-025-00377-3FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinomaTung-Wei Hsu0Wan-Yu Wang1Hsin-An Chen2Tzu-Hsuan Wang3Chih-Ming Su4Po-Hsiang Liao5Alvin Chen6Kuei-Yen Tsai7George Kokotos8Cheng-Chin Kuo9Ching-Feng Chiu10Yen-Hao Su11Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityDepartment of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityDepartment of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityDepartment of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityDepartment of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityCardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationDepartment of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityDepartment of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityDepartment of Chemistry, National and Kapodistrian University of AthensInstitute of Cellular and System Medicine, National Health Research InstitutesDepartment of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityDepartment of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical UniversityAbstract Background Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC. Methods We investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine–resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine–resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259. Results We observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3’untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer. Conclusion Our results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy.https://doi.org/10.1186/s40170-025-00377-3FOXO3aGemcitabine resistanceLactate dehydrogenase AmicroRNA-4259 |
| spellingShingle | Tung-Wei Hsu Wan-Yu Wang Hsin-An Chen Tzu-Hsuan Wang Chih-Ming Su Po-Hsiang Liao Alvin Chen Kuei-Yen Tsai George Kokotos Cheng-Chin Kuo Ching-Feng Chiu Yen-Hao Su FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma Cancer & Metabolism FOXO3a Gemcitabine resistance Lactate dehydrogenase A microRNA-4259 |
| title | FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma |
| title_full | FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma |
| title_fullStr | FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma |
| title_full_unstemmed | FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma |
| title_short | FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma |
| title_sort | foxo3a mir 4259 driven ldha expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma |
| topic | FOXO3a Gemcitabine resistance Lactate dehydrogenase A microRNA-4259 |
| url | https://doi.org/10.1186/s40170-025-00377-3 |
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