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

doi:10.3390/ijms20174087

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Title:	Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy
Authors:	Wang, Hui-Ching Chou, Chia-Lin Ching-Chieh Yang(楊清傑) Huang, Wei-Lun Hsu, Yin-Chou Luo, Chi-Wen Chen, Tzu-Ju Li, Chien-Feng Pan, Mei-Ren
Contributors:	Kaohsiung Med Univ, Coll Med, Grad Inst Clin Med Kaohsiung Med Univ, Div Hematol & Oncol, Dept Internal Med, Kaohsiung Med Univ Hosp Chi Mei Med Ctr, Div Colon & Rectal Surg, Dept Surg Natl Sun Yat Sen Univ, Inst Biomed Sci Chi Mei Med Ctr, Dept Radiat Oncol Chia Nan Univ Pharm & Sci, Dept Pharm Kaohsiung Vet Gen Hosp, Dept Radiat Oncol I Shou Univ, Dept Emergency Med, E Da Hosp Kaohsiung Med Univ Hosp, Div Breast Surg, Dept Surg Chi Mei Med Ctr, Dept Pathol Chung Hwa Univ Med Technol, Dept Optometry Chi Mei Med Ctr, Dept Med Res Natl Hlth Res Inst, Natl Inst Canc Res Kaohsiung Med Univ, Drug Dev & Value Creat Res Ctr
Keywords:	CHD4 CCRT rectal cancers radioresistance
Date:	2019-09
Issue Date:	2020-07-29 13:49:10 (UTC+8)
Publisher:	MDPI
Abstract:	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.
Relation:	International Journal of Molecular Sciences, v.20, n.17, 4087
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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