N-myc downstream-regulated gene 1 promotes apoptosis in colorectal cancer via up-regulating death receptor 4
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Xian Zhang1,2,3,*, Bo Feng3,*, Fan Zhu3,*, Chaoran Yu3, Jiaoyang Lu3, Meng Pan3, Zirui He3, Xiongzhi Wangpu3, Jing Sun3 and Xiao Yang1,2
1Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2Department of General Surgery, Division of Gastrointestinal and Colorectal Surgery, Shanghai East Hospital, Tongji University, Shanghai 200120, China
3Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
*These authors have contributed equally to this work
Xiao Yang, email: [email protected]
Jing Sun, email: [email protected]
Bo Feng, email: [email protected]
Keywords: apoptosis, colorectal cancer, death receptor, NDRG1, TRAIL
Abbreviations: CRC, colorectal cancer; NDRG1, N-myc downstream regulated gene-1; RT-PCR, reverse transcription-polymerase chain reaction; TRAIL, tumor necrosis factor-related apoptosis-inducing ligands; IHC, immunohistochemistry
Received: February 20, 2017 Accepted: May 21, 2017 Published: July 28, 2017
The aim of this study was to evaluate the clinical significance of N-myc downstream-regulated gene 1 (NDRG1) in colorectal cancer (CRC) patients and to explore the mechanisms governing the role of NDRG1 in apoptosis of CRC cells. In the current study, we found that NDRG1 was a prognostic marker of CRC patients. Moreover, NDRG1 expression negatively correlated to tumor size and clinical TNM stage, suggesting that NDRG1 might act as a tumor suppressor by inhibiting proliferation or inducing apoptosis in CRC. Consistently, substantial apoptosis was observed in vitro and in vivo in the presence of NDRG1. From a mechanistic standpoint, we discovered that NDRG1 was able to prevent death receptor 4 from degradation induced by MARCH-8, a member of the membrane-associated RING-CH (MARCH) ubiquitin ligase family. As a consequence, CRC cells expressing NDRG1 were more sensitive to reagents targeting death receptors such as tumor necrosis factor-related apoptosis-inducing ligands (TRAIL). Additionally, the pro-apoptotic effect of NDRG1 was also validated in mouse xenograft model. In conclusion, our results provided further insights of the pivotal role of NDRG1 in apoptosis initiated by death receptors and demonstrated a novel marker to predict the sensitivity of CRC to TRAIL treatment in future clinical study.
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