Abstract
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.
Highlights
Colorectal cancer (CRC) is one of the most prevalent alimentary tract tumors leading to the third cancer-related death across the world [1]
We discovered that N-myc downstream-regulated gene 1 (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
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 colorectal cancer (CRC) to tumor necrosis factor-related apoptosis-inducing ligands (TRAIL) treatment in future clinical study
Summary
Colorectal cancer (CRC) is one of the most prevalent alimentary tract tumors leading to the third cancer-related death across the world [1]. More than 1.2 million patients are diagnosed with CRC every year [2]. Dramatic progress has been achieved in surgery, neoadjuvant therapy, and adjuvant chemotherapy [3]. Despite these improvements, tumor progression is still the major cause of cancer-related death [4]. The identification of molecules regulating cancer cell death in response to chemotherapy is of great importance, as such molecules may constitute important clinical predictive markers of response to chemotherapy or novel therapeutic targets [5]
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