NLRX1
NLR family member X1 precursor (Caterpiller protein 11.3) (CLR11.3) (Nucleotide-binding oligomerization domain protein 26) (Nucleotide-binding oligomerization domain protein 5) (Nucleotide-binding oligomerization domain protein 9) [NOD26] [NOD5] [NOD9]
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This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression. Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with β-galactosidase assays. Kaplan-Meier analyses and Cox regression models were used for prognostic evaluation. NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26-2.76, overall survival [OS] 2.26, 95% CI 1.44-3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner. NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment.
MeSH Terms
- Animals
- Carcinoma, Hepatocellular
- Cell Line, Tumor
- Cellular Senescence
- Epithelial-Mesenchymal Transition
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Liver Neoplasms
- Male
- Mice, Nude
- Middle Aged
- Mitochondrial Proteins
- Phosphatidylinositol 3-Kinases
- Prognosis
- Proto-Oncogene Proteins c-akt
- Signal Transduction
Keywords
- Epithelial-mesenchymal-transition
- Hepatocellular carcinoma
- NLRX1
- Senescence
- Transition
- Tumor suppressor
Nucleotide-binding domain and leucine-rich-repeat-containing family member X1 (NLRX1) is a cytoplasmic pattern recognition receptor that is predominantly located in mitochondria, which is tightly related to mitochondrial damage, reactive oxygen species (ROS) production, inflammation and apoptosis. The present study was designed to explore whether NLRX1 expresses in C57BL/6 mice cochlear hair cells and, if so, to investigate the possible correlations between NLRX1 and hearing. The location and dynamic expression of NLRX1 were investigated by immunofluorescence, real-time PCR and Western blotting. Hearing thresholds of C57BL/6 mice were measured by auditory brainstem response (ABR). Moreover, the downstream inflammatory and apoptotic pathways regulated by NLRX1 were examined in age-related and neomycin-induced hair cell damage. Data showed that NLRX1 expressed in cytoplasm of C57BL/6 cochlear hair cells, especially in the cilia, which were essential for sound sensation. The expression of NLRX1 in hair cells increased as the mice grew up, and, decreased as they aged. Additionally, the activated apoptotic JNK pathway was detected in 9-month old mice with worse-hearing and 3-month old mice treated with neomycin. Overall, results indicate that NLRX1 may relate to hair cell maturity, hearing formation and maintenance, and promote hair cell apoptosis through JNK pathway induced by aging and neomycin.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Anti-Bacterial Agents
- Apoptosis
- Deafness
- Evoked Potentials, Auditory, Brain Stem
- Hair Cells, Auditory
- Mice, Inbred C57BL
- Mitochondrial Proteins
- Neomycin
Keywords
- Apoptosis
- C57BL/6 mice
- Hair cells
- NLRX1
- Nucleotide-binding domain and leucine-rich-repeat-containing family member X1