The tumor suppressor, p53, is a transcription factor which can modulate the transcription of a number of target genes that are involved in cell-cycle arrest and apoptosis. However, the apoptotic pathway mediated by p53 is not fully understood. Here, we showed that N-Myc downstream-regulated gene 2 (NDRG2) is a new target gene that is regulated by p53. NDRG2 mRNA and protein levels can be upregulated in a p53-dependent manner. The first intron of the NDRG2 gene contains a site that binds p53 directly and mediates wild-type p53-dependent transactivation. In addition, silencing of NDRG2 attenuates p53-mediated apoptosis, whereas overexpression of NDRG2 suppresses tumor cell growth, regardless of the presence or absence of p53. Our results indicate that NDRG2 is a novel p53-inducible target that is involved in the p53-mediated apoptosis pathway.

Colorectal cancer is one of the leading causes of cancer death worldwide. According to global genomic status, colorectal cancer can be classified into two main types: microsatellite-stable and microsatellite-instable tumors. Moreover, the two subtypes also exhibit different responses to chemotherapeutic agents through distinctive molecular mechanisms. Recently, mitochondrial DNA depletion has been shown to induce apoptotic resistance in microsatellite-instable colorectal cancer. However, the effects of altered mitochondrial DNA copy number on the progression of microsatellite-stable colorectal cancer, which accounts for the majority of colorectal cancer, remain unclear. In this study, we systematically investigated the functional role of altered mitochondrial DNA copy number in the survival and metastasis of microsatellite-stable colorectal cancer cells. Moreover, the underlying molecular mechanisms were also explored. Our results demonstrated that increased mitochondrial DNA copy number by forced mitochondrial transcription factor A expression significantly facilitated cell proliferation and inhibited apoptosis of microsatellite-stable colorectal cancer cells both in vitro and in vivo. Moreover, we demonstrated that increased mitochondrial DNA copy number enhanced the metastasis of microsatellite-stable colorectal cancer cells. Mechanistically, the survival advantage conferred by increased mitochondrial DNA copy number was caused in large part by elevated mitochondrial oxidative phosphorylation. Furthermore, treatment with oligomycin significantly suppressed the survival and metastasis of microsatellite-stable colorectal cancer cells with increased mitochondrial DNA copy number. Our study provides evidence supporting a possible tumor-promoting role for mitochondrial DNA and uncovers the underlying mechanism, which suggests a potential novel therapeutic target for microsatellite-stable colorectal cancer.

MCUR1 was frequently upregulated in HCC cells to enhance the Ca uptake into mitochondria in an MCU-dependent manner, which significantly facilitated cell survival by inhibiting mitochondria-dependent intrinsic apoptosis and promoting proliferation of HCC cells, and thus led to poor prognosis. In vivo assay confirmed these results, indicating that overexpressed MCUR1 notably decreased the fraction of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and increased the positive Ki67 staining in xenograft tumors, while reduced MCUR1 expression was associated with impaired growth capacity of HCC cells in nude mice. The survival advantage conferred by MCUR1-mediated mitochondrial Ca uptake was majorly caused by elevated production of mitochondrial reactive oxygen species and subsequent AKT/MDM2- induced P53 degradation, which regulated the expression level of apoptosis-related molecules and cell cycle-related molecules. Treatment of mitochondrial Ca-buffering protein parvalbumin remarkably inhibited the growth of HCC cells. Conclusions and Innovation: Our study provides evidence supporting a possible tumor-promoting role for MCUR1-mediated mitochondrial Ca uptake and uncovers a mechanistic understanding that links change of mitochondrial Ca homeostasis to cancer cell survival, which suggests a potential novel therapeutic target for HCC. Antioxid. Redox Signal. 28, 1120-1136.

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Background: Acute ischemic stroke (AIS) is a leading cause of disability and mortality worldwide. Prediction of penumbra existence after AIS is crucial for making decision on reperfusion therapy. Yet a fast, inexpensive, simple, and noninvasive predictive biomarker for the poststroke penumbra with clinical translational potential is still lacking. We aim to investigate whether the CircOGDH (circular RNA derived from oxoglutarate dehydrogenase) is a potential biomarker for penumbra in patients with AIS and its role in ischemic neuronal damage. Methods: CircOGDH was screened from penumbra of middle cerebral artery occlusion mice and was assessed in plasma of patients with AIS by quantitative polymerase chain reaction. Magnetic resonance imaging was used to examine the penumbra volumes. CircOGDH interacted with miR-5112 in primary cortical neurons was detected by fluorescence in situ hybridization, RNA immunoprecipitation, and luciferase reporter assay. ADV-mediated CircOGDH knockdown ameliorated neuronal apoptosis induced by COL4A4 (Gallus collagen, type VI, alpha VI) overexpression. Transmission electron microscope, nanoparticle tracking analysis, and Western blot were performed to confirm exosomes. Results: CircOGDH expression was dramatically and selectively upregulated in the penumbra tissue of middle cerebral artery occlusion mice and in the plasma of 45 patients with AIS showing a 54-fold enhancement versus noncerebrovascular disease controls. Partial regression analysis revealed that CircOGDH expression was positively correlated with the size of penumbra in patients with AIS. Sequestering of miR-5112 by CircOGDH enhanced COL4A4 expression to elevate neuron damage. Additionally, knockdown of CircOGDH significantly enhanced neuronal cell viability under ischemic conditions. Furthermore, the expression of CircOGDH in brain tissue was closely related to that in the serum of middle cerebral artery occlusion mice. Finally, we found that CircOGDH was highly expressed in plasma exosomes of patients with AIS compared with those in noncerebrovascular disease individuals. Conclusions: These results demonstrate that CircOGDH is a potential therapeutic target for regulating ischemia neuronal viability, and is enriched in neuron-derived exosomes in the peripheral blood, exhibiting a predictive biomarker of penumbra in patients with AIS.