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Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy

Neoadjuvant concurrent chemoradiotherapy (CCRT), followed by radical proctectomy, is the standard treatment for locally advanced rectal cancer. However, a poor response and therapeutic resistance continue to occur despite this treatment. In this study, we analyzed the microarray datasets (GSE68204)...

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Autores principales: Wang, Hui-Ching, Chou, Chia-Lin, Yang, Ching-Chieh, Huang, Wei-Lun, Hsu, Yin-Chou, Luo, Chi-Wen, Chen, Tzu-Ju, Li, Chien-Feng, Pan, Mei-Ren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747537/
https://www.ncbi.nlm.nih.gov/pubmed/31438571
http://dx.doi.org/10.3390/ijms20174087
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author Wang, Hui-Ching
Chou, Chia-Lin
Yang, Ching-Chieh
Huang, Wei-Lun
Hsu, Yin-Chou
Luo, Chi-Wen
Chen, Tzu-Ju
Li, Chien-Feng
Pan, Mei-Ren
author_facet Wang, Hui-Ching
Chou, Chia-Lin
Yang, Ching-Chieh
Huang, Wei-Lun
Hsu, Yin-Chou
Luo, Chi-Wen
Chen, Tzu-Ju
Li, Chien-Feng
Pan, Mei-Ren
author_sort Wang, Hui-Ching
collection PubMed
description Neoadjuvant concurrent chemoradiotherapy (CCRT), followed by radical proctectomy, is the standard treatment for locally advanced rectal cancer. However, a poor response and therapeutic resistance continue to occur despite this treatment. In this study, we analyzed the microarray datasets (GSE68204) of rectal cancer from the Gene Expression Omnibus database, and identified CHD4 as one of the most significantly up-regulated genes among all subunits of the nucleosome remodeling and histone deacetylation (NuRD) complex, in non-responders to CCRT, among locally advanced rectal cancer (LARC) patients. We confirmed the predictive and prognostic significance of CHD4 expression in CCRT treatment, and its correlation with other clinicopathological features, such as tumor regression grade (TRG), therapeutic response, and patient survival. This was carried out by immunohistochemical studies on endoscopic biopsy tissues from 172 rectal cancer patients, receiving neoadjuvant concurrent chemoradiotherapy (CCRT). A high expression of CHD4 was significantly associated with pre-treatment tumor status (p < 0.001) and lymph node metastasis (p < 0.001), post-treatment tumor status (p < 0.001), and lymph node metastasis (p < 0.001), vascular invasion (p = 0.042), and tumor regression grade (p = 0.001). A high expression of CHD4 could also predict poor disease-specific survival and metastasis-free survival (log-rank test, p = 0.0373 and p < 0.0001, respectively). In multivariate Cox proportional-hazards regression analysis, CHD4 overexpression was an independent factor of poor prognosis for metastasis-free survival (HR, 4.575; 95% CI, 1.717–12.192; p = 0.002). By in vitro studies, based on cell line models, we also demonstrated that, the overexpression of CHD4 induced radio-resistance in microsatellite instability-high (MSI-H) colorectal cells (CRCs). On the contrary, the knockdown of CHD4 enhanced radiosensitivity in microsatellite stable (MSS) CRCs. Altogether, we have identified CHD4 as an important regulator of radio-resistance in both MSI-H and MSS CRC cell lines.
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spelling pubmed-67475372019-09-27 Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy Wang, Hui-Ching Chou, Chia-Lin Yang, Ching-Chieh Huang, Wei-Lun Hsu, Yin-Chou Luo, Chi-Wen Chen, Tzu-Ju Li, Chien-Feng Pan, Mei-Ren Int J Mol Sci Article Neoadjuvant concurrent chemoradiotherapy (CCRT), followed by radical proctectomy, is the standard treatment for locally advanced rectal cancer. However, a poor response and therapeutic resistance continue to occur despite this treatment. In this study, we analyzed the microarray datasets (GSE68204) of rectal cancer from the Gene Expression Omnibus database, and identified CHD4 as one of the most significantly up-regulated genes among all subunits of the nucleosome remodeling and histone deacetylation (NuRD) complex, in non-responders to CCRT, among locally advanced rectal cancer (LARC) patients. We confirmed the predictive and prognostic significance of CHD4 expression in CCRT treatment, and its correlation with other clinicopathological features, such as tumor regression grade (TRG), therapeutic response, and patient survival. This was carried out by immunohistochemical studies on endoscopic biopsy tissues from 172 rectal cancer patients, receiving neoadjuvant concurrent chemoradiotherapy (CCRT). A high expression of CHD4 was significantly associated with pre-treatment tumor status (p < 0.001) and lymph node metastasis (p < 0.001), post-treatment tumor status (p < 0.001), and lymph node metastasis (p < 0.001), vascular invasion (p = 0.042), and tumor regression grade (p = 0.001). A high expression of CHD4 could also predict poor disease-specific survival and metastasis-free survival (log-rank test, p = 0.0373 and p < 0.0001, respectively). In multivariate Cox proportional-hazards regression analysis, CHD4 overexpression was an independent factor of poor prognosis for metastasis-free survival (HR, 4.575; 95% CI, 1.717–12.192; p = 0.002). By in vitro studies, based on cell line models, we also demonstrated that, the overexpression of CHD4 induced radio-resistance in microsatellite instability-high (MSI-H) colorectal cells (CRCs). On the contrary, the knockdown of CHD4 enhanced radiosensitivity in microsatellite stable (MSS) CRCs. Altogether, we have identified CHD4 as an important regulator of radio-resistance in both MSI-H and MSS CRC cell lines. MDPI 2019-08-21 /pmc/articles/PMC6747537/ /pubmed/31438571 http://dx.doi.org/10.3390/ijms20174087 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Hui-Ching
Chou, Chia-Lin
Yang, Ching-Chieh
Huang, Wei-Lun
Hsu, Yin-Chou
Luo, Chi-Wen
Chen, Tzu-Ju
Li, Chien-Feng
Pan, Mei-Ren
Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy
title Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy
title_full Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy
title_fullStr Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy
title_full_unstemmed Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy
title_short Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy
title_sort over-expression of chd4 is an independent biomarker of poor prognosis in patients with rectal cancers receiving concurrent chemoradiotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747537/
https://www.ncbi.nlm.nih.gov/pubmed/31438571
http://dx.doi.org/10.3390/ijms20174087
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