Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7
Abstract Background Tyrosine kinase inhibitors (TKIs) that specifically target mutational points in the EGFR gene have significantly reduced suffering and provided greater relief to patients with lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, Osimertinib, has been successfully employed i...
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-023-01811-0 |
| _version_ | 1797789929207496704 |
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| author | Kai Li Zi-Yang Peng Rui Wang Xiang Li Ning Du Da-Peng Liu Jia Zhang Yun-Feng Zhang Lei Ma Ye Sun Shou-Ching Tang Hong Ren Yi-Ping Yang Xin Sun |
| author_facet | Kai Li Zi-Yang Peng Rui Wang Xiang Li Ning Du Da-Peng Liu Jia Zhang Yun-Feng Zhang Lei Ma Ye Sun Shou-Ching Tang Hong Ren Yi-Ping Yang Xin Sun |
| author_sort | Kai Li |
| collection | DOAJ |
| description | Abstract Background Tyrosine kinase inhibitors (TKIs) that specifically target mutational points in the EGFR gene have significantly reduced suffering and provided greater relief to patients with lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, Osimertinib, has been successfully employed in clinical treatments to overcome resistance to both original and acquired T790M and L858R mutational points. Nevertheless, the issue of treatment failure response has emerged as an insurmountable problem. Methods By employing a combination of multiple and integrated approaches, we successfully identified a distinct population within the tumor group that plays a significant role in carcinogenesis, resistance, and recurrence. Our research suggests that addressing TKI resistance may involve targeting the renewal and repopulation of stem-like cells. To investigate the underlying mechanisms, we conducted RNA Microarray and m6A Epi-Transcriptomic Microarray analyses, followed by assessment of transcription factors. Additionally, we specifically designed a tag to detect the polypeptide circRNA-AA, and its expression was confirmed through m6A regulations. Results We initially identified unique molecular signatures present in cancer stem cells that contributed to poor therapeutic responses. Activation of the alternative Wnt pathway was found to sustain the renewal and resistant status of these cells. Through bioinformatics analysis and array studies, we observed a significant decrease in the expression of circFBXW7 in Osimertinib-resistant cell lines. Notably, the abnormal expression pattern of circFBXW7 determined the cellular response to Osimertinib. Functional investigations revealed that circFBXW7 inhibits the renewal of cancer stem cells and resensitizes both resistant LUAD cells and stem cells to Osimertinib. In terms of the underlying mechanism, we discovered that circFBXW7 can be translated into short polypeptides known as circFBXW7-185AA. These polypeptides interact with β-catenin in an m6A-dependent manner. This interaction leads to reduced stability of β-catenin by inducing subsequent ubiquitination, thereby suppressing the activation of canonical Wnt signaling. Additionally, we predicted that the m6A reader, YTHDF3, shares common binding sites with hsa-Let-7d-5p. Enforced expression of Let-7d post-transcriptionally decreases the levels of YTHDF3. The repression of Let-7d by Wnt signaling releases the stimulation of m6A modification by YTHDF3, promoting the translation of circFBXW7-185AA. This creates a positive feedback loop contributing to the cascade of cancer initiation and promotion. Conclusions Our bench study, in vivo experiments, and clinical validation have unequivocally shown that circFBXW7 effectively inhibits the abilities of LUAD stem cells and reverses resistance to TKIs by modulating Wnt pathway functions through the action of circFBXW7-185AA on β-catenin ubiquitination and inhibition. The regulatory role of circRNA in Osimertinib treatment has been rarely reported, and our findings reveal that this process operates under the influence of m6A modification. These results highlight the tremendous potential of this approach in enhancing therapeutic strategies and overcoming resistance to multiple TKI treatments. |
| first_indexed | 2024-03-13T01:57:37Z |
| format | Article |
| id | doaj.art-9e59868997854687b75b0b68eeaca4e6 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-13T01:57:37Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-9e59868997854687b75b0b68eeaca4e62023-07-02T11:09:22ZengBMCMolecular Cancer1476-45982023-07-0122111510.1186/s12943-023-01811-0Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7Kai Li0Zi-Yang Peng1Rui Wang2Xiang Li3Ning Du4Da-Peng Liu5Jia Zhang6Yun-Feng Zhang7Lei Ma8Ye Sun9Shou-Ching Tang10Hong Ren11Yi-Ping Yang12Xin Sun13Department of Otorhinolaryngology-Head and Neck Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversitySchool of Future Technology, National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, Department of Thoracic Surgery & Oncology, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Otorhinolaryngology-Head and Neck Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, Department of Thoracic Surgery & Oncology, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, Department of Thoracic Surgery & Oncology, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, Department of Thoracic Surgery & Oncology, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, Department of Thoracic Surgery & Oncology, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Anesthesiology & Perioperative Medicine, Operating Centre, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Anesthesiology & Operation, Operating Centre, the First Affiliated Hospital of Xi’an Jiaotong UniversityLSU School of Medicine, LSU-LCMC Cancer CenterDepartment of Thoracic Surgery, Department of Thoracic Surgery & Oncology, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Radiotherapy, Shaanxi Provincial Tumor HospitalDepartment of Thoracic Surgery, Department of Thoracic Surgery & Oncology, the First Affiliated Hospital of Xi’an Jiaotong UniversityAbstract Background Tyrosine kinase inhibitors (TKIs) that specifically target mutational points in the EGFR gene have significantly reduced suffering and provided greater relief to patients with lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, Osimertinib, has been successfully employed in clinical treatments to overcome resistance to both original and acquired T790M and L858R mutational points. Nevertheless, the issue of treatment failure response has emerged as an insurmountable problem. Methods By employing a combination of multiple and integrated approaches, we successfully identified a distinct population within the tumor group that plays a significant role in carcinogenesis, resistance, and recurrence. Our research suggests that addressing TKI resistance may involve targeting the renewal and repopulation of stem-like cells. To investigate the underlying mechanisms, we conducted RNA Microarray and m6A Epi-Transcriptomic Microarray analyses, followed by assessment of transcription factors. Additionally, we specifically designed a tag to detect the polypeptide circRNA-AA, and its expression was confirmed through m6A regulations. Results We initially identified unique molecular signatures present in cancer stem cells that contributed to poor therapeutic responses. Activation of the alternative Wnt pathway was found to sustain the renewal and resistant status of these cells. Through bioinformatics analysis and array studies, we observed a significant decrease in the expression of circFBXW7 in Osimertinib-resistant cell lines. Notably, the abnormal expression pattern of circFBXW7 determined the cellular response to Osimertinib. Functional investigations revealed that circFBXW7 inhibits the renewal of cancer stem cells and resensitizes both resistant LUAD cells and stem cells to Osimertinib. In terms of the underlying mechanism, we discovered that circFBXW7 can be translated into short polypeptides known as circFBXW7-185AA. These polypeptides interact with β-catenin in an m6A-dependent manner. This interaction leads to reduced stability of β-catenin by inducing subsequent ubiquitination, thereby suppressing the activation of canonical Wnt signaling. Additionally, we predicted that the m6A reader, YTHDF3, shares common binding sites with hsa-Let-7d-5p. Enforced expression of Let-7d post-transcriptionally decreases the levels of YTHDF3. The repression of Let-7d by Wnt signaling releases the stimulation of m6A modification by YTHDF3, promoting the translation of circFBXW7-185AA. This creates a positive feedback loop contributing to the cascade of cancer initiation and promotion. Conclusions Our bench study, in vivo experiments, and clinical validation have unequivocally shown that circFBXW7 effectively inhibits the abilities of LUAD stem cells and reverses resistance to TKIs by modulating Wnt pathway functions through the action of circFBXW7-185AA on β-catenin ubiquitination and inhibition. The regulatory role of circRNA in Osimertinib treatment has been rarely reported, and our findings reveal that this process operates under the influence of m6A modification. These results highlight the tremendous potential of this approach in enhancing therapeutic strategies and overcoming resistance to multiple TKI treatments.https://doi.org/10.1186/s12943-023-01811-0Translated circRNAsm6A modificationTyrosine kinase inhibitorLung adenocarcinomaTherapy resistance |
| spellingShingle | Kai Li Zi-Yang Peng Rui Wang Xiang Li Ning Du Da-Peng Liu Jia Zhang Yun-Feng Zhang Lei Ma Ye Sun Shou-Ching Tang Hong Ren Yi-Ping Yang Xin Sun Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7 Molecular Cancer Translated circRNAs m6A modification Tyrosine kinase inhibitor Lung adenocarcinoma Therapy resistance |
| title | Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7 |
| title_full | Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7 |
| title_fullStr | Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7 |
| title_full_unstemmed | Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7 |
| title_short | Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7 |
| title_sort | enhancement of tki sensitivity in lung adenocarcinoma through m6a dependent translational repression of wnt signaling by circ fbxw7 |
| topic | Translated circRNAs m6A modification Tyrosine kinase inhibitor Lung adenocarcinoma Therapy resistance |
| url | https://doi.org/10.1186/s12943-023-01811-0 |
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