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N-myc downstream-regulated gene 1 promotes apoptosis in colorectal cancer via up-regulating death receptor 4.

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.

SUBMITTER: Zhang X

PROVIDER: S-EPMC5669913 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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N-myc downstream-regulated gene 1 promotes apoptosis in colorectal cancer via up-regulating death receptor 4.

Zhang Xian X Feng Bo B Zhu Fan F Yu Chaoran C Lu Jiaoyang J Pan Meng M He Zirui Z Wangpu Xiongzhi X Sun Jing J Yang Xiao X

Oncotarget 20170728 47

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 apopto ...[more]

PMID: 29137287

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Project description:Background: The mitochondrial transporter SLC25A39 has been implicated in the import of mitochondrial glutathione (mGSH) from the cytoplasm, crucial for mitigating oxidative stress and preserving mitochondrial function. Despite the well-established involvement of mitochondria in cancer, the functional impact of SLC25A39 on CRC progression remains elusive. Methods: The mRNA and protein expressions were detected by PCR, immunohistochemistry, and Western blot, respectively. Cell activity, cell proliferation, colony formation, and apoptosis were measured by CCK8 assay, EdU incorporation assay, plated colony formation assay, and flow cytometry, respectively. Cell migration was detected by wound healing and transwell chamber assay. The tumor microenvironment (TME), immune checkpoint molecules, and drug sensitivity of CRC patients were investigated using R language, GraphPad Prism 8 and online databases. Results: Here, we report a significant upregulation of SLC25A39 expression in CRC. Functional assays revealed that overexpression of SLC25A39 promoted CRC cell proliferation and migration while inhibiting apoptosis. Conversely, SLC25A39 knockdown suppressed cell growth and migration while enhancing apoptosis in vitro. Additionally, reduced SLC25A39 expression attenuated tumor growth in xenograft models. Mechanistically, elevated SLC25A39 levels correlated with reduced reactive oxygen species (ROS) accumulation in CRC. Furthermore, bioinformatic analyses unveiled the high SLC25A39 levels was associated with decreased expression of immune checkpoints and reduced responsiveness to immunotherapy. Single-cell transcriptomic profiling identified diverse cellular expression patterns of SLC25A39 and related immune regulators. Lastly, drug sensitivity analysis indicated potential therapeutic avenues targeting SLC25A39 in CRC. Conclusion Our findings underscore the pivotal role of SLC25A39 in CRC progression and suggest its candidacy as a therapeutic target in CRC management.

Project description:Host cells harbor various intrinsic mechanisms to restrict viral infections as a first line of antiviral defense. Viruses have evolved various countermeasures against these antiviral mechanisms. Here we show that N-Myc downstream-regulated gene 1 (NDRG1) limits productive hepatitis C virus (HCV) infection by inhibiting viral assembly. Interestingly, HCV infection downregulates NDRG1 protein and mRNA expression. The loss of NDRG1 increases the size and number of lipid droplets, which are the sites of HCV assembly. HCV suppresses NDRG1 expression by upregulating MYC, which directly inhibits the transcription of NDRG1 The upregulation of MYC also leads to the reduced expression of the NDRG1-specific kinase serum/glucocorticoid-regulated kinase 1 (SGK1), resulting in a markedly diminished phosphorylation of NDRG1. The knockdown of MYC during HCV infection rescues NDRG1 expression and phosphorylation, suggesting that MYC regulates NDRG1 at both the transcriptional and posttranslational levels. Overall, our results suggest that NDRG1 restricts HCV assembly by limiting lipid droplet formation. HCV counteracts this intrinsic antiviral mechanism by downregulating NDRG1 via a MYC-dependent mechanism.IMPORTANCE Hepatitis C virus (HCV) is an enveloped single-stranded RNA virus that targets hepatocytes in the liver. HCV is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, and estimates suggest a global prevalence of 2.35%. Up to 80% of acutely infected individuals will develop chronic infection, and as many as 5% eventually progress to liver cancer. An understanding of the mechanisms behind virus-host interactions and viral carcinogenesis is still lacking. The significance of our research is that it identifies a previously unknown relationship between HCV and a known tumor-associated gene. Furthermore, our data point to a new role for this gene in the liver and in lipid metabolism. Thus, HCV infection serves as a great biological model to advance our knowledge of liver functions and the development of liver cancer.

Dataset Information

N-myc downstream-regulated gene 1 promotes apoptosis in colorectal cancer via up-regulating death receptor 4.

Publications

N-myc downstream-regulated gene 1 promotes apoptosis in colorectal cancer via up-regulating death receptor 4.

Similar Datasets

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