Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used for patients with EGFR-mutated lung cancer. Despite its initial therapeutic efficacy, most patients eventually develop drug resistance, which leads to a poor prognosis in lung cancer patients. Previous investigat...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-04-01
|
| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.851391/full |
| _version_ | 1818009521131356160 |
|---|---|
| author | Dandan Ding Jufeng Zhang Zhiming Luo Huazhen Wu Huazhen Wu Zexiao Lin Weicheng Liang Xingyang Xue |
| author_facet | Dandan Ding Jufeng Zhang Zhiming Luo Huazhen Wu Huazhen Wu Zexiao Lin Weicheng Liang Xingyang Xue |
| author_sort | Dandan Ding |
| collection | DOAJ |
| description | Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used for patients with EGFR-mutated lung cancer. Despite its initial therapeutic efficacy, most patients eventually develop drug resistance, which leads to a poor prognosis in lung cancer patients. Previous investigations have proved that non-coding RNAs including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) contribute to drug resistance by various biological functions, whereas how they regulate EGFR-TKI resistance remains unclear. In this study, we examined gene expression using the microarray technology on gefitinib-resistant NSCLC cells to obtain differentially expressed (DE) lncRNAs and mRNAs. A total of 45 DE-lncRNAs associated with overall survival and 1799 target DE-mRNAs were employed to construct a core lncRNA–miRNA–mRNA network to illustrate underlying molecular mechanisms of how EGFR-TKI resistance occurs in NSCLC. We found that target DE-mRNAs were mainly enriched in pathways involved in EGFR-TKI resistance, especially the target DE-mRNAs regulated by LINC01128 were significantly enriched in the PI3K/Akt signaling pathway, where the synergy of these target DE-mRNAs may play a key role in EGFR-TKI resistance. In addition, downregulated LINC01128, acting as a specific miRNA sponge, decreases PTEN via sponging miR-25-3p. Furthermore, signaling reactions caused by the downregulation of PTEN would activate the PI3K/Akt signaling pathway, which may lead to EGFR-TKI resistance. In addition, a survival analysis indicated the low expression of LINC01128, and PTEN is closely related to poor prognosis in lung adenocarcinoma (LUAD). Therefore, the LINC01128/miR-25-3p/PTEN axis may promote EGFR-TKI resistance via the PI3K/Akt signaling pathway, which provides new insights into the underlying molecular mechanisms of drug resistance to EGFR-TKIs in NSCLC. In addition, our study sheds light on developing novel therapeutic approaches to overcome EGFR-TKI resistance in NSCLC. |
| first_indexed | 2024-04-14T05:42:54Z |
| format | Article |
| id | doaj.art-481ba12eb79341d9b1d4995d52c78569 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-14T05:42:54Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-481ba12eb79341d9b1d4995d52c785692022-12-22T02:09:22ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-04-011310.3389/fgene.2022.851391851391Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLCDandan Ding0Jufeng Zhang1Zhiming Luo2Huazhen Wu3Huazhen Wu4Zexiao Lin5Weicheng Liang6Xingyang Xue7Department of Thoracic Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, ChinaDepartment of Thoracic Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, ChinaDepartment of Thoracic Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, ChinaDepartment of Thoracic Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, ChinaQingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, ChinaDepartment of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaBiotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Thoracic Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, ChinaEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used for patients with EGFR-mutated lung cancer. Despite its initial therapeutic efficacy, most patients eventually develop drug resistance, which leads to a poor prognosis in lung cancer patients. Previous investigations have proved that non-coding RNAs including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) contribute to drug resistance by various biological functions, whereas how they regulate EGFR-TKI resistance remains unclear. In this study, we examined gene expression using the microarray technology on gefitinib-resistant NSCLC cells to obtain differentially expressed (DE) lncRNAs and mRNAs. A total of 45 DE-lncRNAs associated with overall survival and 1799 target DE-mRNAs were employed to construct a core lncRNA–miRNA–mRNA network to illustrate underlying molecular mechanisms of how EGFR-TKI resistance occurs in NSCLC. We found that target DE-mRNAs were mainly enriched in pathways involved in EGFR-TKI resistance, especially the target DE-mRNAs regulated by LINC01128 were significantly enriched in the PI3K/Akt signaling pathway, where the synergy of these target DE-mRNAs may play a key role in EGFR-TKI resistance. In addition, downregulated LINC01128, acting as a specific miRNA sponge, decreases PTEN via sponging miR-25-3p. Furthermore, signaling reactions caused by the downregulation of PTEN would activate the PI3K/Akt signaling pathway, which may lead to EGFR-TKI resistance. In addition, a survival analysis indicated the low expression of LINC01128, and PTEN is closely related to poor prognosis in lung adenocarcinoma (LUAD). Therefore, the LINC01128/miR-25-3p/PTEN axis may promote EGFR-TKI resistance via the PI3K/Akt signaling pathway, which provides new insights into the underlying molecular mechanisms of drug resistance to EGFR-TKIs in NSCLC. In addition, our study sheds light on developing novel therapeutic approaches to overcome EGFR-TKI resistance in NSCLC.https://www.frontiersin.org/articles/10.3389/fgene.2022.851391/fullEGFR-TKIsdrug resistancelong non-coding RNALINC01128lung cancer-diagnosis |
| spellingShingle | Dandan Ding Jufeng Zhang Zhiming Luo Huazhen Wu Huazhen Wu Zexiao Lin Weicheng Liang Xingyang Xue Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC Frontiers in Genetics EGFR-TKIs drug resistance long non-coding RNA LINC01128 lung cancer-diagnosis |
| title | Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC |
| title_full | Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC |
| title_fullStr | Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC |
| title_full_unstemmed | Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC |
| title_short | Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC |
| title_sort | analysis of the lncrna mirna mrna network reveals a potential regulatory mechanism of egfr tki resistance in nsclc |
| topic | EGFR-TKIs drug resistance long non-coding RNA LINC01128 lung cancer-diagnosis |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.851391/full |
| work_keys_str_mv | AT dandanding analysisofthelncrnamirnamrnanetworkrevealsapotentialregulatorymechanismofegfrtkiresistanceinnsclc AT jufengzhang analysisofthelncrnamirnamrnanetworkrevealsapotentialregulatorymechanismofegfrtkiresistanceinnsclc AT zhimingluo analysisofthelncrnamirnamrnanetworkrevealsapotentialregulatorymechanismofegfrtkiresistanceinnsclc AT huazhenwu analysisofthelncrnamirnamrnanetworkrevealsapotentialregulatorymechanismofegfrtkiresistanceinnsclc AT huazhenwu analysisofthelncrnamirnamrnanetworkrevealsapotentialregulatorymechanismofegfrtkiresistanceinnsclc AT zexiaolin analysisofthelncrnamirnamrnanetworkrevealsapotentialregulatorymechanismofegfrtkiresistanceinnsclc AT weichengliang analysisofthelncrnamirnamrnanetworkrevealsapotentialregulatorymechanismofegfrtkiresistanceinnsclc AT xingyangxue analysisofthelncrnamirnamrnanetworkrevealsapotentialregulatorymechanismofegfrtkiresistanceinnsclc |