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BackgroundIn recent years, papillary thyroid carcinoma is considered to be one of the fastest increaseing cancer. NDRG family member 3 (NDRG3) has been proposed as a molecular marker of tumor, and is expected to be used in clinic.MethodsEnzyme-linked immunosorbent assay was used to detect the serum NDRG3 expression in 81 papillary thyroid carcinoma cases, 75 benign thyroid nodules cases and 77 healthy control cases, respectively. Electrochemiluminescence method was applied to measure the levels of triiodothyronine, tetraiodothyronine, thyrotropin, thyroglobulin antibody and thyroid peroxidase antibody. Immunohistochemical staining was used to detect the expression of NDRG3 in papillary thyroid carcinoma, benign thyroid nodules and normal tissues adjacent to cancer.ResultsThe expression of serum triiodothyronine, tetraiodothyronine, thyrotropin, thyroglobulin antibody and thyroid peroxidase antibody and NDRG3 were significantly different among benign thyroid nodules, papillary thyroid carcinoma cases and healthy control groups (P

N-Myc downstream regulated gene 3 (NDRG3) is a unique pro-tumorigenic member among NDRG family genes, mediating growth signals. Here, we investigated the pathophysiological roles of NDRG3 in relation to cell metabolism by disrupting its functions in liver. Mice with liver-specific KO of NDRG3 (Ndrg3 LKO) exhibited glycogen storage disease (GSD) phenotypes including excessive hepatic glycogen accumulation, hypoglycemia, elevated liver triglyceride content, and several signs of liver injury. They suffered from impaired hepatic glucose homeostasis, due to the suppression of fasting-associated glycogenolysis and gluconeogenesis. Consistently, the expression of glycogen phosphorylase (PYGL) and glucose-6-phosphate transporter (G6PT) was significantly down-regulated in an Ndrg3 LKO-dependent manner. Transcriptomic and metabolomic analyses revealed that NDRG3 depletion significantly perturbed the methionine cycle, redirecting its flux towards branch pathways to upregulate several metabolites known to have hepatoprotective functions. Mechanistically, Ndrg3 LKO-dependent downregulation of glycine N-methyltransferase in the methionine cycle and the resultant elevation of the S-adenosylmethionine level appears to play a critical role in the restructuring of the methionine metabolism, eventually leading to the manifestation of GSD phenotypes in Ndrg3 LKO mice. Our results indicate that NDRG3 is required for the homeostasis of liver cell metabolism upstream of the glucose–glycogen flux and methionine cycle and suggest therapeutic values for regulating NDRG3 in disorders with malfunctions in these pathways. [ABSTRACT FROM AUTHOR]

Abstract Background Osteoarthritis (OA), as a common disease, seriously affects the quality of life of the victims, but its pathogenesis remains unclear. It has been confirmed that hypoxia-induced factor (HIF)-mediated hypoxia response plays an important role in the development and progression of OA. As a member of the N-myc downstream regulatory gene families, NDRG3 has been reported to independently regulate the hypoxic response of tumour cells, but the relationship between NDRG3 and OA development has not been reported so far. Methods In this study, seven OA patients were admitted to Guizhou Provincial People’s Hospital from January 2017 to December 2018. The OA group included 5 patients clinically diagnosed with hip/knee OA, which required arthroplasty. The normal group included 2 patients with no previous history of OA and rheumatoid arthritis, which required amputation due to trauma or tumour. The articular cartilage samples were collected to detect the expression of HIF-1α, HIF-2α and NDRG3 using immunohistochemical (IHC), haematoxylin and eosin (HE) and toluidine blue (TB) staining. Results HE and TB staining indicated that the cartilage surface of the normal group was smooth and intact, with a columnar arrangement of hyaline chondrocytes, while the cartilage surface of the OA group was discontinuous, with cartilage missing and fibrous soft tissue growing into the defect site. HIF-1α staining was positive in both groups. Moreover, HIF-2α and NDRG3 staining was weakly positive in the normal group, but were uniformly and strongly positive in the OA group. The positively stained areas and integral optical density for NDRG3 were significantly greater in OA group than in the normal group (p

Purpose It is generally accepted that long noncoding RNAs (lncRNAs) function as vital regulators of tumor development and progression. Long intergenic non‐coding RNA 1410 (LINC01410) is a newly discovered lncRNA, and its role in osteosarcoma (OS) is yet to be determined. Materials and methods: The expression of LINC01410, microRNA‐122‐5p (miR‐122‐5p), and N‐myc downstream‐regulated gene 3 (NDRG3) in OS tissues was determined using reverse transcription‐quantitative PCR. Interactions between LINC01410, miR‐122‐5p, and NDRG3 were predicted and verified using bioinformatics tools and luciferase assays. Cell proliferation, migration, and invasion were detected using cell counting Kit‐8 and Transwell assays. Results: LINC01410 was overexpressed in OS tissues. Furthermore, it was confirmed that LINC01410 facilitated OS cell proliferation and migration. Our studies also showed that LINC01410 binds to miR‐122‐5p, and miR‐122‐5p binds to NDRG3. Finally, we observed that LINC01410 knockdown inhibited the proliferation, invasion, and migration of OS cells. Knockdown of LINC01410 resulted in the upregulation of miR‐122‐5p and downregulation of NDRG3. Conclusion: Our results demonstrated that the LINC01410/miR‐122‐5p/NDRG3 axis is involved in the progression of OS. [ABSTRACT FROM AUTHOR]

N-Myc downstream regulated gene 3 (NDRG3) is a unique pro-tumorigenic member among NDRG family genes, mediating growth signals. Here, we investigated the pathophysiological roles of NDRG3 in relation to cell metabolism by disrupting its functions in liver. Mice with liver-specific KO of NDRG3 (Ndrg3 LKO) exhibited glycogen storage disease (GSD) phenotypes including excessive hepatic glycogen accumulation, hypoglycemia, elevated liver triglyceride content, and several signs of liver injury. They suffered from impaired hepatic glucose homeostasis, due to the suppression of fasting-associated glycogenolysis and gluconeogenesis. Consistently, the expression of glycogen phosphorylase (PYGL) and glucose-6-phosphate transporter (G6PT) was significantly down-regulated in an Ndrg3 LKO-dependent manner. Transcriptomic and metabolomic analyses revealed that NDRG3 depletion significantly perturbed the methionine cycle, redirecting its flux towards branch pathways to upregulate several metabolites known to have hepatoprotective functions. Mechanistically, Ndrg3 LKO-dependent downregulation of glycine N-methyltransferase in the methionine cycle and the resultant elevation of the S-adenosylmethionine level appears to play a critical role in the restructuring of the methionine metabolism, eventually leading to the manifestation of GSD phenotypes in Ndrg3 LKO mice. Our results indicate that NDRG3 is required for the homeostasis of liver cell metabolism upstream of the glucose–glycogen flux and methionine cycle and suggest therapeutic values for regulating NDRG3 in disorders with malfunctions in these pathways.

The N-Myc downstream-regulated gene (NDRG) family belongs to the α/β-hydrolase fold and is known to exert various physiologic functions in cell proliferation, differentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 Å resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the α/β-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the α/β-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix α6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3. [ABSTRACT FROM AUTHOR]

Highlights • Expression of miR-1b in injured sciatic nerve was significantly downregulated after sciatic nerve injury. • NDRG3 is the direct target gene of miR-1b. • miR-1b overexpression and NDRG3 knockdown inhibited the proliferation and migration of SCs. • miR-1b mediated SCs proliferation/migration/apoptosis through NDRG3. • Downregulation of miR-1b promoted the function recovery after sciatic nerve injury. Abstract Peripheral nerve injury (PNI) is a global problem that leads to severe disability and high healthcare expenditure. Accumulating evidence suggested that the phenotypes of Schwann cells (SCs) could be regulated by microRNAs (miRNAs) and expressions of various miRNAs are altered after PNI. In this study, the expression of miR-1b in the injured nerve and hypoxia-treated SCs was detected through qRT-PCR. The target genes of miR-1b were predicted by bioinformatics prediction and dual-luciferase reporter assay and verified through qRT-PCR and western blot. The effects of miR-1b and its specific target gene on the proliferation, migration and apoptosis of SCs were determined and the regulation of miR-1b on peripheral nerve regeneration after PNI was further investigated in vivo. We found that miR-1b was obviously downregulated in the injured nerve in a rat sciatic nerve transection model and directly targeted N-myc downstream-regulated gene 3 (NDRG3) by binding to its 3′-UTR and caused both mRNA degradation and translation suppression of NDRG3. Overexpression of miR-1b or knockdown of NDRG3 decreased the proliferation and migration as well as increased the apoptosis of SCs. NDRG3 reversed the effects of miR-1b overexpression on proliferation/migration/apoptosis of RSC96. In addition, injection of miR-1b antagomir promoted the expression of NDRG3 in the injured nerve following sciatic nerve injury. Compared to the model group, the rats treated with miR-1b agomir had lower functional recovery rate, and downregulation of miR-1b through injection of specific antagomir improved the functional recovery rate according to the results of sciatic functional index and nerve conduction velocity. Overall, our results will contribute to the development of novel targets for promoting nerve regeneration after PNI. [ABSTRACT FROM AUTHOR]

Decidualization is an indispensable event in the embryo implantation process, but its underlying molecular mechanisms remain elusive. In this study, we showed that in mice, the uterine expression of N-myc downstream-regulated gene 3 (NDRG3), a member of the α/β hydrolase superfamily, was induced by estradiol and progesterone. During the embryo implantation process, uterine Ndrg3 expression was remarkably upregulated, and its expression level at implantation sites (IS) was significantly higher than that at inter-IS. Increased uterine expression of Ndrg3 was associated with artificial decidualization and the activation of delayed implantation. The in vitro decidualization of mouse endometrial stromal cells (ESCs) induced by estradiol and progesterone was also accompanied by increased Ndrg3 expression, and downregulated Ndrg3 expression in ESCs effectively inhibited decidualization. miR-290b-5p was identified as an upstream regulator of Ndrg3, and the uterine expression level of miR-290b-5p was decreased during the implantation process. Furthermore, overexpression of miR-290b-5p in mouse ESCs inhibited their in vitro decidualization. Taken together, these data suggested that Ndrg3 might play an important role in embryo implantation by regulating decidualization potentially via the estrogen/progesterone/miR-290b-5p pathway. [ABSTRACT FROM AUTHOR]

Background: NDRG3 is an N-myc downregulated gene (NDRG). The aim of this article was to identify the role of NDRG3 in colorectal cancer (CRC) and to determine the mechanism underlying its function. Methods: Using immunohistochemical staining, expression and clinicopathological variables of NDRG3 were analyzed in 170 CRC samples. Overexpression of NDRG3 was employed in SW1116 cells, downregulation of NDRG3 was achieved in RKO cells, then migration and invasion assays were performed in vitro, and a mouse model was constructed in vivo. Results: Increased expression of NDRG3 was observed in primary CRC tissues, and this expression was correlated with distant metastasis. Consistently, ectopic expression of NDRG3 in SW1116 cells enhanced cell migration and invasion, while knockdown of NDRG3 in RKO cells significantly suppressed CRC cell metastasis. The portal vein injection models suggested that NDRG3 overexpression facilitates liver metastasis. These events were associated with the phosphorylation of Src (c-Src) at Tyr 419 site. Conclusion: Our results showed that NDRG3 facilitates CRC migration and invasion by activating Src phosphorylation, suggesting the role of NDRG3 as a candidate oncogene. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: N-myc downstream-regulated gene 3 (NDRG3) is one of the important members of the NDRG family which crucially take part in cell proliferation, differentiation and other biological processes. METHODS: In this present study, western-blotting analysis was performed to evaluate NDRG3 expression in NSCLC cell lines. One-step quantitative reverse transcription-polymerase chain reaction (qPCR) with 16 fresh-frozen NSCLC samples and immunohistochemistry (IHC) analysis in 100 NSCLC cases were conducted to explore the relationship between NDRG3 expression and the clinicopathological characteristics of NSCLC. RESULTS: NDRG3 expression levels were statistically higher in NSCLC cell lines and tissue samples, compared with that of in non-cancerous cell line and tissue samples (p < 0.05). The IHC data demonstrated that the NDRG3 expression was significantly correlated with pathological grade (p = 0.038), N (p = 0.020) and TNM stage (p = 0.002). Survival analysis and Kaplan-Meier curve indicated that NDRG3 expression (p = 0.002) and T (p = 0.047) were independently associated with the unfavorable overall survival of patients with NSCLC. CONCLUSIONS: The data implied that NDRG3 expression may be identified as a new predictor in NSCLC prognosis. [ABSTRACT FROM AUTHOR]

BACKGROUNDS: Hepatocellular carcinoma (HCC) is an epithelial cancer that originates from hepatocytes and it is the most common primary malignant tumor of the liver. Till now the prognosis of HCC patients is generally poor. The molecular mechanism giving rise to HCC development and recurrence is still largely unknown. MicroRNA-31 (miR-31) is among the most commonly altered microRNAs in human cancers, and alternations of miR-31 expression were reported to play pivotal roles in tumorigenesis and tumor progression. METHODS: In this work, the primary biological function of miR-31 in HCC tumorigenesis was investigated. RESULTS: Our data showed that overexpression of miR-31 induced markedly inhibition of HCC cell proliferation, migration in vitro and inhibited xenograft tumor growth in vivo. One target gene of miR-31, NDRG3, was also demonstrated indispensable for HCC cell survival. Furthermore, miR-31 and NDRG3 were both essential for HCC cell drug resistance in adriamycin. CONCLUSIONS: We conclude that miR-31 is a crucial regulator in hepatocellular carcinoma, miR-31 and its target gene NDRG3 may be potential therapeutic targets for HCC treatment in the future. [ABSTRACT FROM AUTHOR]

Purpose of Review: The relationship between colonic bacteria and the host is symbiotic, but how communication between the two partners occurs is just beginning to be understood at the molecular level. Here, we highlight specific products of bacterial metabolism that are present in the colonic lumen and their molecular targets in the host that facilitate this communication. Recent Findings: Colonic epithelial cells and mucosal immune cells express several cell surface receptors and nuclear receptors that are activated by specific bacterial metabolites, which impact multiple signaling pathways and expression of many genes. In addition, some bacterial metabolites also possess the ability to cause epigenetic changes in these cells via inhibition of selective enzymes involved in the maintenance of histone acetylation and DNA methylation patterns. Summary: Colonic bacteria communicate with their host with selective metabolites that interact with host molecular targets. This chemical communication underlies a broad range of the biology and function of colonic epithelial cells and mucosal immune cells, which protect against inflammation and carcinogenesis in the colon under normal physiological conditions. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment. [ABSTRACT FROM AUTHOR]

Background: In recent years, papillary thyroid carcinoma is considered to be one of the fastest increaseing cancer. NDRG family member 3 (NDRG3) has been proposed as a molecular marker of tumor, and is expected to be used in clinic., Methods: Enzyme-linked immunosorbent assay was used to detect the serum NDRG3 expression in 81 papillary thyroid carcinoma cases, 75 benign thyroid nodules cases and 77 healthy control cases, respectively. Electrochemiluminescence method was applied to measure the levels of triiodothyronine, tetraiodothyronine, thyrotropin, thyroglobulin antibody and thyroid peroxidase antibody. Immunohistochemical staining was used to detect the expression of NDRG3 in papillary thyroid carcinoma, benign thyroid nodules and normal tissues adjacent to cancer., Results: The expression of serum triiodothyronine, tetraiodothyronine, thyrotropin, thyroglobulin antibody and thyroid peroxidase antibody and NDRG3 were significantly different among benign thyroid nodules, papillary thyroid carcinoma cases and healthy control groups ( P < 0.001). Only the expression of serum NDRG3 was significantly different between benign thyroid nodules and papillary thyroid carcinoma groups ( P < 0.001). Immunohistochemistry showed that NDRG3 was expressed in all three groups, the lowest in papillary thyroid carcinoma, the second in benign thyroid nodules, and the highest in normal tissues adjacent to cancer. Logistic regression analysis showed that serum NDRG3 was an independent protective factor for papillary thyroid carcinoma (OR =0.964, 95%CI =0.953 to 0.974, P < 0.001). The ROC curve of non-papillary thyroid carcinoma diagnosed by serum NDRG3 showed the optimal cut-off value of 481.38 pg/ml, sensitivity of 72.4%, specificity of 90.1%, and the maximum area under the curve (AUC =0.902, 95%CI =0.863 to 0.940, P < 0.001). The ROC curve of benign thyroid nodules diagnosed by serum NDRG3 showed the optimal critical value of 459.28 pg/ml, sensitivity of 81.3%, and specificity of 74.1% (AUC =0.863, 95%CI =0.808 to 0.919, P < 0.001). The expression level of serum NDRG3 was significantly correlated with extrathyroid extensionand ( P = 0.007) and lymphatic metastasis of papillary thyroid carcinoma ( P =0.019)., Conclusions: The decrease of NDRG3 expression can not only differential diagnosis benign thyroid nodules and papillary thyroid carcinoma, but also serve as a molecular marker for the diagnosis of papillary thyroid carcinoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wang, Quan, Liu, Tian and Dong.)

Abstract: The N-myc downstream-regulated genes, NDRG3 and NDRG4, are suggested to play important roles in biological processes and pathogenesis. Expression of NDRG3 and NDRG4 has been shown to be reduced or absent in numerous cancer cell lines and tumor types, suggesting that they may exert function as a tumor suppressor gene. In this review, we will summarize the current research on NDRG3 and NDRG4, including the molecular structure, cellular and tissue distribution, biological function, and function in cancer. We tried to show their significance in studying disease and their therapeutic potential. [Copyright &y& Elsevier]

Objective: To study expression of NDRG3 in prostatic mesenchyma and effect of exogenous NDRG3 on prostatic stromal cells. Methods: Immunohistochemical analysis was used to check expression of NDRG3 in prostate mesnenchyma. The WPMY-1 prostate immortalized mesenchyma cell line was stably-transfected with a NDRG3 gene expression vector. The NDRG3-stable transfected WPMY-1 sublines were studied along with parental and empty vector transfected WPMY-1 cells as controls. RT-PCR technology was applied to identity downstream gene expression under regulation of NDRG3 expression. Results: Expression of DNRG3 was observed in prostate cancer mesenchyma, over-expression of NDRG3 in WPMY-1 cell up-regulated expression of chemotatic factors-CXCL3 and CXCL5. Conclusion: Expression of stromal NDRG3 in prostate cancer specimens is significantly higher than that in benign prostatic hypertrophy (BPH) sample. There is a remarkable difference between the two groups of samples, NDRG3 may be related to angiogenesis in prostatic mesenchyma. [Copyright &y& Elsevier]

Cells have evolved an elaborate DNA repair network to ensure complete and accurate DNA replication. Defects in these repair machineries can fuel genome instability and drive carcinogenesis while creating vulnerabilities that may be exploited in therapy. Here, we use nascent chromatin capture (NCC) proteomics to characterize the repair of replication-associated DNA double-strand breaks (DSBs) triggered by topoisomerase 1 (TOP1) inhibitors. We reveal profound changes in the fork proteome, including the chromatin environment and nuclear membrane interactions, and identify three classes of repair factors according to their enrichment at broken and/or stalled forks. ATM inhibition dramatically rewired the broken fork proteome, revealing that ataxia telangiectasia mutated (ATM) signalling stimulates DNA end resection, recruits PLK1, and concomitantly suppresses the canonical DSB ubiquitination response by preventing accumulation of RNF168 and BRCA1-A. This work and collection of replication fork proteomes provide a new framework to understand how cells orchestrate homologous recombination repair of replication-associated DSBs. • Comprehensive proteomics of replication forks damaged by TOP1 inhibition • Broken and stalled forks show distinct repairomes and chromatin environments • Rewiring of the broken fork proteome by ATM inhibition toward DSB ubiquitination • PLK1, NDRG3, and UBAP2 are promoting repair of broken forks by HR By systematic proteomics profiling of replication forks challenged by the topoisomerase I inhibitor camptothecin, Nakamura et al. identify dedicated repair factors for broken replication forks, characterize their chromatin environment, and reveal that ATM and PLK1 promote homologous recombination by suppressing the canonical DNA double-strand break ubiquitination response at broken forks. [ABSTRACT FROM AUTHOR]

The heart manifests hypertrophic growth in response to high blood pressure, which may decompensate and progress to heart failure under persistent stress. Metabolic remodeling is an early event in this process. However, its role remains to be fully characterized. Here, we show that lactate dehydrogenase A (LDHA), a critical glycolytic enzyme, is elevated in the heart in response to hemodynamic stress. Cardiomyocyte-restricted deletion of LDHA leads to defective cardiac hypertrophic growth and heart failure by pressure overload. Silencing of LDHA in cultured cardiomyocytes suppresses cell growth from pro-hypertrophic stimulation in vitro , while overexpression of LDHA is sufficient to drive cardiomyocyte growth. Furthermore, we find that lactate is capable of rescuing the growth defect from LDHA knockdown. Mechanistically, lactate stabilizes NDRG3 (N-myc downregulated gene family 3) and stimulates ERK (extracellular signal-regulated kinase). Our results together suggest that the LDHA/NDRG3 axis may play a critical role in adaptive cardiomyocyte growth in response to hemodynamic stress. • Metabolic remodeling plays an important role in hypertensive heart disease • LDHA as a key enzyme of glycolysis is increased in the hypertrophic heart • Deficiency of LDHA exacerbates cardiomyopathy under pressure overload • LDHA may be required for adaptive hypertrophic growth via NDRG3 stimulation Dai et al. find that LDHA is significantly increased in the heart under hemodynamic stress, and cardiomyocyte-specific deletion of LDHA leads to severe cardiac dysfunction in response to pressure overload. LDHA may govern adaptive growth through elevation of NDRG3 and activation of ERK. [ABSTRACT FROM AUTHOR]

The N-Myc downstream-regulated gene (NDRG) family belongs to the α/β-hydrolase fold and is known to exert various physiologic functions in cell proliferation, differentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 Å resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the α/β-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the α/β-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix α6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3.

N-myc downstream-regulated gene 3 (NDRG3), an important member of the NDRG family, is involved in cell proliferation, differentiation, and other biological processes. The present study analyzed NDRG3 expression in hepatocellular carcinoma (HCC) and explored the relationship between expression of NDRG3 in HCC patients and their clinicopathological characteristics. We performed quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry (IHC) analyses on HCC tissues to elucidate NDRG3 expression characteristics in HCC patients. Kaplan-Meier survival curve and Cox regression analyses were used to evaluate the prognoses of 102 patients with HCC. The results revealed that compared with non-tumor tissues, HCC tissues showed significantly higher NDRG3 expression. In addition, our analyses showed that NDRG3 expression was statistically associated with tumor size ( P =0.048) and pathological grade ( P =0.001). Survival analysis and Kaplan-Meier curves revealed that NDRG3 expression is an independent prognostic indicator for disease-free survival ( P =0.002) and overall survival ( P =0.005) in HCC patients. The data indicate that NDRG3 expression may be considered as a oncogenic biomarker and a novel predictor for HCC prognosis., (© 2018 The Author(s).)

Fasting-refeeding in mice induces transient hyperproliferation of colonic epithelial cells, which is dependent on the lactate produced as a metabolite of commensal bacteria. We attempted to manipulate colonic epithelial cell turnover with intermittent fasting to prompt recovery from acute colitis. Acute colitis was induced in C57BL/6 mice by administration of dextran sulfate sodium in the drinking water for 5 days. From day 6, mice were fasted for 36 h and refed normal bait, glucose powder, or lactylated high-amylose starch. On day 9, colon tissues were subjected to analysis of histology and cytokine expression. The effect of lactate on the proliferation of colonocytes was assessed by enema in vivo and primary culture in vitro . Intermittent fasting resulted in restored colonic crypts and less expression of interleukin-1β and interleukin-17 in the colon than in mice fed ad libitum . Administration of lactate in the colon at refeeding time by enema or by feeding lactylated high-amylose starch increased the number of regenerating crypts. Addition of lactate but not butyrate or acetate supported colony formation of colonocytes in vitro . In conclusion, intermittent fasting in the resolution phase of acute colitis resulted in better recovery of epithelial cells and reduced inflammation., Competing Interests: No potential conflicts of interest were disclosed.

Backgrounds: Hepatocellular carcinoma (HCC) is an epithelial cancer that originates from hepatocytes and it is the most common primary malignant tumor of the liver. Till now the prognosis of HCC patients is generally poor. The molecular mechanism giving rise to HCC development and recurrence is still largely unknown. MicroRNA-31 (miR-31) is among the most commonly altered microRNAs in human cancers, and alternations of miR-31 expression were reported to play pivotal roles in tumorigenesis and tumor progression., Methods: In this work, the primary biological function of miR-31 in HCC tumorigenesis was investigated., Results: Our data showed that overexpression of miR-31 induced markedly inhibition of HCC cell proliferation, migration in vitro and inhibited xenograft tumor growth in vivo. One target gene of miR-31, NDRG3, was also demonstrated indispensable for HCC cell survival. Furthermore, miR-31 and NDRG3 were both essential for HCC cell drug resistance in adriamycin., Conclusions: We conclude that miR-31 is a crucial regulator in hepatocellular carcinoma, miR-31 and its target gene NDRG3 may be potential therapeutic targets for HCC treatment in the future.

N-myc downstream-regulated gene 3 (NDRG3), which belongs to the NDRG family, is believed to play important roles in human cancer. In this present study, one-step quantitative reverse transcription-polymerase chain reaction (qPCR) and western blotting tests with 10 fresh-frozen laryngeal squamous cell carcinoma (LSCC) samples and immunohistochemistry (IHC) analysis in 109 LSCC cases were performed to investigate the relationship between NDRG3 expression and the clinicopathological characteristics of LSCC. Results demonstrated that NDRG3 mRNA and protein expression levels were statistically higher in LSCC tissues than that in non-cancerous tissues (all p<0.05). IHC data showed that the NDRG3 protein expression was remarkably correlated with lymph node metastasis (p=0.043). Univariate and multivariate survival analysis implied that high NDRG3 expression (p=0.004), lymph node metastasis (p=0.044) and TNM stage (p=0.020) were independently associated with the unfavourable overall survival of patients with LSCC. The above findings suggested that NDRG3 may be identified as a novel biomarker predicting the prognosis of LSCC., (Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment., Competing Interests: The authors declare no conflict of interest.