TY - JOUR
T1 - Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma
AU - Lee, Yu Cheng
AU - Lin, Cheng Han
AU - Chang, Wei Lun
AU - Lin, Wen Der
AU - Pan, Jhih Kai
AU - Wang, Wei Jan
AU - Su, Bor Chyuan
AU - Chung, Hsien Hui
AU - Tsai, Chen Hsun
AU - Lin, Forn Chia
AU - Wang, Wen Ching
AU - Lu, Pei Jung
N1 - Funding Information:
The funding support from the Ministry of Science and Technology, Taiwan (MOST 109-2320-B-038-012-MY2) and Taipei Medical University (TMU108-AE1-B24) to YC Lee; (MOST 104-2314-B-006-074) and (105-2314-B-006-045-MY2) to FCL. Additionally, Chi Mei Medical Center provided funding (CMNCKU10506). Acknowledgments: We thank National Cheng Kung University Hospital (Tainan, Taiwan) for assisting with ESCC clinical specimens? collection.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
KW - acquired concurrent chemoradiotherapy resistance
KW - cell plasticity
KW - epithelial to mesenchymal conversion
KW - esophageal cancer
KW - microRNA
UR - http://www.scopus.com/inward/record.url?scp=85128125261&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128125261&partnerID=8YFLogxK
U2 - 10.3390/ijms23084367
DO - 10.3390/ijms23084367
M3 - Article
C2 - 35457185
AN - SCOPUS:85128125261
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 8
M1 - 4367
ER -
