Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma
Esophageal squamous cell carcinoma (ESCC) is a common and fatal malignancy with an increasing incidence worldwide. Over the past decade, concurrent chemoradiotherapy (CCRT) with or without surgery is an emerging therapeutic approach for locally advanced ESCC. Unfortunately, many patients exhibit poo...
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2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/8/4367 |
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| author | Yu-Cheng Lee Cheng-Han Lin Wei-Lun Chang Wen-Der Lin Jhih-Kai Pan Wei-Jan Wang Bor-Chyuan Su Hsien-Hui Chung Chen-Hsun Tsai Forn-Chia Lin Wen-Ching Wang Pei-Jung Lu |
| author_facet | Yu-Cheng Lee Cheng-Han Lin Wei-Lun Chang Wen-Der Lin Jhih-Kai Pan Wei-Jan Wang Bor-Chyuan Su Hsien-Hui Chung Chen-Hsun Tsai Forn-Chia Lin Wen-Ching Wang Pei-Jung Lu |
| author_sort | Yu-Cheng Lee |
| collection | DOAJ |
| description | Esophageal squamous cell carcinoma (ESCC) is a common and fatal malignancy with an increasing incidence worldwide. Over the past decade, concurrent chemoradiotherapy (CCRT) with or without surgery is an emerging therapeutic approach for locally advanced ESCC. Unfortunately, many patients exhibit poor response or develop acquired resistance to CCRT. Once resistance occurs, the overall survival rate drops down rapidly and without proper further treatment options, poses a critical clinical challenge for ESCC therapy. Here, we utilized lab-created CCRT-resistant cells as a preclinical study model to investigate the association of chemoradioresistantresistance with miRNA-mediated cell plasticity alteration, and to determine whether reversing EMT status can re-sensitize refractory cancer cells to CCRT response. During the CCRT treatment course, refractory cancer cells adopted the conversion of epithelial to mesenchymal phenotype; additionally, miR-200 family members were found significantly down-regulated in CCRT resistance cells by miRNA microarray screening. Down-regulated miR-200 family in CCRT resistance cells suppressed E-cadherin expression through snail and slug, and accompany with an increase in N-cadherin. Rescuing expressions of miR-200 family members in CCRT resistance cells, particularly in miR-200b and miR-200c, could convert cells to epithelial phenotype by increasing E-cadherin expression and sensitize cells to CCRT treatment. Conversely, the suppression of miR-200b and miR-200c in ESCC cells attenuated E-cadherin, and that converted cells to mesenchymal type by elevating N-cadherin expression, and impaired cell sensitivity to CCRT treatment. Moreover, the results of ESCC specimens staining established the clinical relevance that higher N-cadherin expression levels associate with the poor CCRT response outcome in ESCC patients. Conclusively, miR-200b and miR-200c can modulate the conversion of epithelial–mesenchymal phenotype in ESCC, and thereby altering the response of cells to CCRT treatment. Targeting epithelial–mesenchymal conversion in acquired CCRT resistance may be a potential therapeutic option for ESCC patients. |
| first_indexed | 2024-03-09T10:34:03Z |
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| id | doaj.art-5e670e19418e4885843afcf492832948 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:34:03Z |
| publishDate | 2022-04-01 |
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| spelling | doaj.art-5e670e19418e4885843afcf4928329482023-12-01T21:04:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01238436710.3390/ijms23084367Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell CarcinomaYu-Cheng Lee0Cheng-Han Lin1Wei-Lun Chang2Wen-Der Lin3Jhih-Kai Pan4Wei-Jan Wang5Bor-Chyuan Su6Hsien-Hui Chung7Chen-Hsun Tsai8Forn-Chia Lin9Wen-Ching Wang10Pei-Jung Lu11Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanInstitute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35 Xiaodong Rd., Tainan 704, TaiwanInstitute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35 Xiaodong Rd., Tainan 704, TaiwanInstitute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35 Xiaodong Rd., Tainan 704, TaiwanInstitute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35 Xiaodong Rd., Tainan 704, TaiwanDepartment of Biological Science and Technology, Research Center for Cancer Biology, China Medical University, Taichung 404, TaiwanDepartment of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanPreventive Medicine Program, Center for General Education, Chung Yuan Christian University, Taoyuan City 320, TaiwanInstitute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35 Xiaodong Rd., Tainan 704, TaiwanDepartment of Radiation Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan 704, TaiwanDepartment of Surgery, Chi Mei Medical Center, No. 901, Zhonghua Rd., Yongkang Dist., Tainan 710, TaiwanInstitute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35 Xiaodong Rd., Tainan 704, TaiwanEsophageal squamous cell carcinoma (ESCC) is a common and fatal malignancy with an increasing incidence worldwide. Over the past decade, concurrent chemoradiotherapy (CCRT) with or without surgery is an emerging therapeutic approach for locally advanced ESCC. Unfortunately, many patients exhibit poor response or develop acquired resistance to CCRT. Once resistance occurs, the overall survival rate drops down rapidly and without proper further treatment options, poses a critical clinical challenge for ESCC therapy. Here, we utilized lab-created CCRT-resistant cells as a preclinical study model to investigate the association of chemoradioresistantresistance with miRNA-mediated cell plasticity alteration, and to determine whether reversing EMT status can re-sensitize refractory cancer cells to CCRT response. During the CCRT treatment course, refractory cancer cells adopted the conversion of epithelial to mesenchymal phenotype; additionally, miR-200 family members were found significantly down-regulated in CCRT resistance cells by miRNA microarray screening. Down-regulated miR-200 family in CCRT resistance cells suppressed E-cadherin expression through snail and slug, and accompany with an increase in N-cadherin. Rescuing expressions of miR-200 family members in CCRT resistance cells, particularly in miR-200b and miR-200c, could convert cells to epithelial phenotype by increasing E-cadherin expression and sensitize cells to CCRT treatment. Conversely, the suppression of miR-200b and miR-200c in ESCC cells attenuated E-cadherin, and that converted cells to mesenchymal type by elevating N-cadherin expression, and impaired cell sensitivity to CCRT treatment. Moreover, the results of ESCC specimens staining established the clinical relevance that higher N-cadherin expression levels associate with the poor CCRT response outcome in ESCC patients. Conclusively, miR-200b and miR-200c can modulate the conversion of epithelial–mesenchymal phenotype in ESCC, and thereby altering the response of cells to CCRT treatment. Targeting epithelial–mesenchymal conversion in acquired CCRT resistance may be a potential therapeutic option for ESCC patients.https://www.mdpi.com/1422-0067/23/8/4367acquired concurrent chemoradiotherapy resistancemicroRNAepithelial to mesenchymal conversionesophageal cancercell plasticity |
| spellingShingle | Yu-Cheng Lee Cheng-Han Lin Wei-Lun Chang Wen-Der Lin Jhih-Kai Pan Wei-Jan Wang Bor-Chyuan Su Hsien-Hui Chung Chen-Hsun Tsai Forn-Chia Lin Wen-Ching Wang Pei-Jung Lu Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma International Journal of Molecular Sciences acquired concurrent chemoradiotherapy resistance microRNA epithelial to mesenchymal conversion esophageal cancer cell plasticity |
| title | Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma |
| title_full | Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma |
| title_fullStr | Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma |
| title_full_unstemmed | Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma |
| title_short | Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma |
| title_sort | concurrent chemoradiotherapy driven cell plasticity by mir 200 family implicates the therapeutic response of esophageal squamous cell carcinoma |
| topic | acquired concurrent chemoradiotherapy resistance microRNA epithelial to mesenchymal conversion esophageal cancer cell plasticity |
| url | https://www.mdpi.com/1422-0067/23/8/4367 |
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