Search Results (73)

Glioblastoma (GBM) is the most prevalent and devastating form of primary brain tumors in adults, with dismal survival despite advancements in treatment modalities. The current study sought to develop clinically significant prognostic models for GBM patients by comprehensively profiling MGMT, NUPR1, NDRG2, and GLI1 gene promoter methylation in GBM tissues vs. non-neurooncological disease (NND) and their association with clinical characteristics and therapeutic outcome. This was further evaluated by in silico functional enrichment analysis. NUPR1, NDRG2, and GLI1 gene promoter methylation were significant epigenetic discriminators between GBM and NND. However, NDRG2 methylation was the sole independent predictor for neoplastic lesions (OR = 1.71, 95% CI [1.25–3.57], p = 0.028). Multivariable Cox regression analysis revealed that NUPR1 promoter hypermethylation was significantly correlated with a lower risk of mortality (HR = 0.96, 95% CI [0.96–0.99], p = 0.002), while multiple tumor sites were linked to an increased risk of mortality in the univariate model (HR = 4.44, 95% CI [1.42–13.88], p = 0.01). A heatmap correlation matrix identified a robust positive correlation among the MGMT and NUPR1 methylation status (r = 0.93, p < 0.001). NUPR1 and MGMT promoter hypermethylation was associated with a favorable response to temozolomide therapy. Patients with NUPR1 and MGMT hypermethylation exhibited extended OS and PFS compared to those with hypomethylation levels, whereas GLI1 and NDRG2 hypermethylation were linked to shorter PFS. In conclusion, the multi-faceted epigenetic panel adopted in the current study captures different aspects of GBM biology and moves towards a more comprehensive model that reflects the molecular heterogeneity of GBM as insights for personalized therapy. Full article

Background/Objectives: Colorectal cancer (CRC) is a major contributor to cancer-related deaths worldwide. While existing screening tools are effective, their high cost and limited availability restrict widespread adoption, particularly in low- and middle-income settings. The identification of affordable, non-invasive biomarkers is therefore critical to improve early CRC detection and survival outcomes. Methods: A systematic literature search was performed through PubMed, ScienceDirect, Medline, ISI Web of Knowledge, and Google Scholar to identify studies reporting stool- and blood-based biomarkers for CRC detection. Data were extracted using a standardized template, including study details, specimen type, detection method, and diagnostic performance parameters such as sensitivity and specificity. Results: DNA methylation biomarkers demonstrated high diagnostic potential. Syndecan 2 (SDC2) and Short Stature Homeobox 2 (SHOX2) achieved a combined stool sensitivity of 91.35%. Other methylation markers, including NDRG4, SEPT9, and BCAT1, showed a composite sensitivity of 82.7%. Plasma-based methylation markers such as GATA5, FOXE1, and SYNE1 reported sensitivities ranging from 18–47% and specificities of 93–99%. Hypermethylation of SFRP2 and WIF-1 achieved 81.3% sensitivity in CRC and precursor lesions. Matrix metalloproteinases (MMP-2 and MMP-9) were elevated in CRC patients, with stool MMP-9 yielding 72.2% sensitivity and 95% specificity. A stool gene panel (UBE2N, IMPDH1, DYNC1LI1, HRASLS2) reached 96.6% sensitivity and 89.7% specificity, while a methylation-based panel (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, VIM) achieved 90.7% sensitivity. MicroRNAs (miR-21, miR-92a, miR-223, miR-182) showed excellent diagnostic performance, with sensitivities exceeding 96% and specificities above 75%. Conclusions: DNA methylation and microRNA biomarkers hold strong promises for non-invasive CRC screening. Multi-marker panels demonstrate superior diagnostic accuracy and may provide a cost-effective, scalable approach for early CRC detection in resource-limited settings. Full article

Background/Objectives: Myogenesis, the process by which myoblasts differentiate into multinucleated muscle fibers, is tightly regulated by transcription factors, signaling pathways, and metabolic cues. Among these, fatty acids have emerged as key regulators beyond their traditional role as energy substrates. Oleic acid, a monounsaturated fatty acid, has been shown to modulate muscle differentiation, potentially influencing myogenic pathways. This study examines the role of oleic acid in promoting C2C12 myoblast differentiation and its associated molecular mechanisms, comparing it to standard horse serum (HS)-based differentiation protocols. Methods: C2C12 murine myoblasts were cultured under proliferative conditions and differentiated using DMEM supplemented with either 2% HS or oleic acid (C18:1, n-9). The molecular signaling pathway was evaluated by measuring the expression of p38 MAPK, β-catenin, GLUT4, and NDRG1. Results: Oleic acid promoted the differentiation of C2C12 cells, as evidenced by a progressively elongated morphology, as well as the induction of muscle-specific myogenin, myosin heavy chain (MHC), and MyoD. Moreover, oleic acid reduced the expression of Atrogin-1 and MuRF1 ubiquitin E3 ligase. BODIPY staining revealed the enhanced accumulation of lipid droplets in oleic acid-treated cells. The Western blot analysis demonstrated robust activation of p38 MAPK and β-catenin pathways in response to oleic acid, compared with HS. Additionally, oleic acid upregulated GLUT4 expression and increased the phosphorylation of insulin receptor and NDRG1, indicating an enhanced glucose uptake capacity. Conclusions: These findings demonstrate that oleic acid promotes C2C12 myoblast differentiation and improves glucose uptake via GLUT4. Oleic acid emerges as a promising metabolic regulator of myogenesis, offering potential therapeutic applications for muscle regeneration in muscle-related pathologies. Full article

Background: Colorectal cancer (CRC) is a term that refers to the combination of colon and rectal cancer as they are being treated as a single tumor. In CRC, 72% of tumors are colon cancer, while the other 28% represent rectal cancer. CRC is a multifactorial disease caused by both genetic and epigenetic changes in the colon mucosal cells, affecting the oncogenes, DNA repair genes, and tumor suppressor genes. Currently, two DNA methylation-based biomarkers for CRC have received FDA approval: SEPT9, used in blood-based screening tests, and a combination of NDRG4 and BMP3 for stool-based tests. Although DNA methylation biomarkers have been explored in colorectal cancer (CRC), the identification of robust and clinically valuable biomarkers remains a challenge, particularly for early-stage detection and precancerous lesions. Patients often receive diagnoses at the locally advanced stage, which limits the potential utility of current biomarkers in clinical settings. Methods: The datasets used in this study were retrieved from the GEO database, specifically GSE75548 and GSE75546 for rectal cancer and GSE50760 and GSE101764 for colon cancer, summing up to a total of 130 paired samples. These datasets represent expression profiling by array, methylation profiling by genome tiling array, and expression profiling by high-throughput sequencing and include rectal and colon cancer samples paired with adjacent normal tissue samples. Differential analysis was used to identify differentially methylated CPG sites (DMCs) and identify differentially expressed genes (DEGs). Results: From the integration of DMCs with DEGs in colorectal cancer, we identified 150 candidates for methylation-regulated genes (MRGs) with two genes common across all cohorts (GNG7 and PDX1) highlighted as candidate biomarkers in CRC. The functional enrichment analysis and protein–protein interactions (PPIs) identified relevant pathways involved in CRC, including the Wnt signaling pathway, extracellular matrix (ECM) organization, among other enriched pathways. Conclusions: Our findings show the strength of our in silco computational approach in jointly identifying methylation-regulated biomarkers for colon cancer and highlight several genes and pathways as biomarker candidates for further investigations. Full article

The N-Myc Downstream Regulated Gene 1 (NDRG1) protein, a member of a family of four, has emerged as a key regulator of various physiological and pathological processes. Extensive knowledge has been gained on the modulation of NDRG1 expression during endoplasmic reticulum stress, autophagy, and hypoxia. Moreover, new functions have emerged in recent years. Notably, NDRG1 regulates cell differentiation, metabolism, autophagy and vesicular transport. This has raised interest in the molecular mechanisms that control the cellular levels and activity of NDRG1. A series of studies have shown that NDRG1 can be finely regulated at the transcriptional, post-transcriptional, and translational levels. In addition, processes that mediate protein degradation and clearance also play key roles. Furthermore, three different NDRG1 proteoforms with distinct functions have been identified. An important question is the extent to which these proteoforms contribute to the regulation of cellular functions. Given the growing clinical interest in NDRG1, this review provides an overview of the regulatory mechanisms that control NDRG1 abundance, helping to deepen our understanding of the complex mechanisms underlying protein regulation. Full article

Toxic chemicals and epigenetic biomarkers associated with cancer have been used successfully in clinical diagnostic screening of feces and urine from individuals, but they have been underutilized in a global setting. We analyzed peer-reviewed literature to achieve the following: (i) compile epigenetic biomarkers of disease, (ii) explore whether research locations are geographically aligned with disease hotspots, and (iii) determine the potential for tracking disease-associated epigenetic biomarkers. Studies (n = 1145) of epigenetic biomarkers (n = 146) in urine and feces from individuals have established notable diagnostic potential for detecting and tracking primarily gastric and urinary cancers. Panels with the highest sensitivity and specificity reported more than once were SEPT9 (78% and 93%, respectively) and the binary biomarker combinations GDF15, TMEFF2, and VIM (93% and 95%), NDRG4 and BMP3 (98% and 90%), and TWIST1 and NID2 (76% and 79%). Screening for epigenetic biomarkers has focused on biospecimens from the U.S., Europe, and East Asia, whereas data are limited in regions with similar/higher disease incidence rates (i.e., data for New Zealand, Japan, and Australia for colorectal cancer). The epigenetic markers discussed here may aid in the future monitoring of multiple cancers from individual- to population-level scales by leveraging the emerging science of wastewater-based epidemiology (WBE). Full article

Background/Objectives: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in various physiological and pathological processes of the ovary. However, the timing of HIF-1α expression and its specific biological function in the follicular development of the human ovary remain unclear. Therefore, in this study, we aimed to examine whether HIF-1α and its downstream gene, N-myc downstream-regulated gene 1 (NDRG1), exhibit stage-specific expression during the follicular development process in the human ovary. Methods: We used ovarian tissues from eight women with regular menstrual cycles who were not undergoing hormonal treatment. We investigated HIF-1α and NDRG1 expression and localization using immunohistochemistry. Further, we transfected human ovarian granulosa (KGN) cells with HIF-1α small interfering RNA (siRNA) to investigate the influence of HIF-1α on NDRG1 expression and progesterone synthesis. Results: The immunohistochemical analysis of human ovarian tissues revealed that HIF-1α was localized in the cytoplasm of granulosa cells (GCs) at both the primary and secondary follicular stages. Conversely, in tertiary and later developmental stages, HIF-1α was observed exclusively in the nucleus of GCs. Furthermore, while NDRG1 was not detected in primary follicles, it was present in all GCs beyond the tertiary stage. Notably, transfection of KGN cells with HIF-1α siRNA significantly decreased NDRG1 expression, at both the mRNA and protein levels, and in progesterone synthesis. Conclusion: Our results indicate that HIF-1α and NDRG1 are integral to follicular development and the early luteinization of pre-ovulatory follicles. Full article

Heterobimetallic complexes of an ambidentate deferiprone derivative, 3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one (PyPropHpH), incorporating an octahedral [Co(4N)]³⁺ (4N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa)) and a half-sandwich type [(η⁶-p-cym)Ru]²⁺ (p-cym = p-cymene) entity have been synthesized and characterized by various analytical techniques. The reaction between PyPropHpH and [Co(4N)Cl]Cl₂ resulted in the exclusive (O,O) coordination of the ligand to Co(III) yielding [Co(tren)PyPropHp](PF₆)₂ (1) and [Co(tpa)PyPropHp](PF₆)₂ (2). This binding mode was further supported by the molecular structure of [Co(tpa)PyPropHp]₂(ClO₄)₃(OH)·6H₂O (5) and [Co(tren)PyPropHpH]Cl(PF₆)₂·2H₂O·C₂H₅OH (6), respectively, obtained via the slow evaporation of the appropriate reaction mixtures and analyzed using X-ray crystallography. Subsequent treatment of 1 or 2 with [Ru(η⁶-p-cym)Cl₂]₂ in a one-pot reaction afforded the corresponding heterobimetallic complexes, [Co(tren)PyPropHp(η⁶-p-cym)RuCl](PF₆)₃ (3) and [Co(tpa)PyPropHp(η⁶-p-cym)RuCl](PF₆)₃ (4), in which the piano-stool Ru core is coordinated by the (N,N) chelating set of the ligand. Cyclic voltammetric measurements revealed that the tpa complexes can be reduced at less negative potentials, suggesting their capability to be bioreductively activated under hypoxia (1% O₂). Hypoxia activation of 2 and 4 was demonstrated by cytotoxicity studies on the MCF-7 human breast cancer cell line. PyPropHpH was shown to be a typical iron-chelating anticancer agent, raising the mRNA levels of TfR1, Ndrg1 and p21. Further qRT-PCR studies provided unambiguous evidence for the bioreduction of 2 after 72 h incubation under hypoxia, in which the characteristic gene induction profile caused by the liberated iron-sequestering PyPropHpH was observed. Full article

Charcot–Marie–Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims. Full article

Drug resistance is a major challenge in the treatment of advanced cholangiocarcinoma (CCA). Understanding the mechanisms of drug resistance can aid in identifying novel prognostic biomarkers and therapeutic targets to improve treatment efficacy. This study established 5-fluorouracil- (5-FU) and gemcitabine-resistant CCA cell lines, KKU-213FR and KKU-213GR, and utilized comparative proteomics to identify differentially expressed proteins in drug-resistant cells compared to parental cells. Additionally, bioinformatics analyses were conducted to explore the biological and clinical significance of key proteins. The drug-resistant phenotypes of KKU-213FR and KKU-213GR cell lines were confirmed. In addition, these cells demonstrated increased migration and invasion abilities. Proteomics analysis identified 81 differentially expressed proteins in drug-resistant cells, primarily related to binding functions, biological regulation, and metabolic processes. Protein–protein interaction analysis revealed a highly interconnected network involving MET, LAMB1, ITGA3, NOTCH2, CDH2, and NDRG1. siRNA-mediated knockdown of these genes in drug-resistant cell lines attenuated cell migration and cell invasion abilities and increased sensitivity to 5-FU and gemcitabine. The mRNA expression of these genes is upregulated in CCA patient samples and is associated with poor prognosis in gastrointestinal cancers. Furthermore, the functions of these proteins are closely related to the epithelial–mesenchymal transition (EMT) pathway. These findings elucidate the potential molecular mechanisms underlying drug resistance and tumor progression in CCA, providing insights into potential therapeutic targets. Full article

Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (Min^ApcΔ716/+) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAF^V600E mutation (BRAF^F-V600ELgr5^{tm1(Cre/ERT2)Cle}Min^ApcΔ716/+, BLM) or knocking out Msh2 (Msh2^LoxP/LoxPVil1-creMin^ApcΔ716/+, MSH2KO) in the Min model altered colon tumor differentiation. Using single-cell RNA sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single-cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the tumor stem cell population. Interestingly, the tumor stem cell population of BLM tumors had revival colon stem cell characteristics with low WNT signaling and an increase in RevCSC marker gene expression. In contrast, MSH2KO tumors were characterized by an increased tumor stem cell population that had higher WNT signaling activity compared to Min tumors. Furthermore, overall BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we identified additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer. Full article

Anoikis, a form of apoptosis resulting from the loss of cell–extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the epigenetic regulation of this process remains to be explored. Here, we demonstrate that the histone deacetylase sirtuin 6 (SIRT6) plays a pivotal role in conferring anoikis resistance to colorectal cancer (CRC) cells. The protein level of SIRT6 is negatively correlated with anoikis in CRC cells. The overexpression of SIRT6 decreases while the knockdown of SIRT6 increases detachment-induced anoikis. Mechanistically, SIRT6 inhibits the transcription of N-myc downstream-regulated gene 1 (NDRG1), a negative regulator of the AKT signaling pathway. We observed the up-regulation of SIRT6 in advanced-stage CRC samples. Together, our findings unveil a novel epigenetic program regulating the anoikis of CRC cells. Full article

The N-myc downstream regulated gene family (NDRGs) includes four members: NDRG1, NDRG2, NDRG3, and NDRG4. These members exhibit 53–65% amino acid identity. The role of NDRGs in tumor growth and metastasis appears to be tumor- and context-dependent. While many studies have reported that these family members have tumor suppressive roles, recent studies have demonstrated that NDRGs, particularly NDRG1 and NDRG2, function as oncogenes, promoting tumor growth and metastasis. Additionally, NDRGs are involved in regulating different signaling pathways and exhibit diverse cellular functions in breast cancers. In this review, we comprehensively outline the oncogenic and tumor suppressor roles of the NDRG family members in breast cancer, examining evidence from in vitro and in vivo breast cancer models as well as tumor tissues from breast cancer patients. We also present analyses of publicly available genomic and transcriptomic data from multiple independent cohorts of breast cancer patients. Full article

DNA methylation (DNAm) is associated with the reproductive system. However, the genetic mechanism through which DNAm regulates gene expression and thus affects litter size in goats is unclear. Therefore, in the present work, genome-wide DNAm profiles of HP and LP Jining Grey goat ovary tissues were comprehensively analyzed via WGBS, and RNA-Seq data were combined to identify candidate genes associated with litter size traits in the Jining Grey goat. Finally, BSP and RT-qPCR were used to verify the sequencing results of the key genes. Notably, the DNMT genes were downregulated at the expression level in the HP group. Both groups exhibited comparable levels of methylation. A total of 976 differentially methylated regions (DMRs) (973 DMRs for CG and 3 DMRs for CHG) and 310 differentially methylated genes (DMGs) were identified in this study. Through integration of WGBS and RNA-Seq data, we identified 59 differentially methylated and differentially expressed genes (DEGs) and ultimately screened 8 key DMGs (9 DMRS) associated with litter size traits in Jining Grey goats (SERPINB2: chr24_62258801_62259000, NDRG4: chr18_27599201_27599400, CFAP43: chr26_27046601_27046800, LRP1B. chr2_79720201_79720400, EPHA6: chr1_40088601_40088800, TTC29: chr17_59385801_59386000, PDE11A: chr2_117418601_117418800 and PGF: chr10_ 16913801_16914000 and chr10_16916401_16916600). In summary, our research comprehensively analyzed the genome-wide DNAm profiles of HP and LP Jining Grey goat ovary tissues. The data findings suggest that DNAm in goat ovaries may play an important role in determining litter size. Full article

N-myc downstream-regulated gene 2 (NDRG2), which is a tumour suppressor, is frequently lost in many types of tumours, including adult T-cell leukaemia/lymphoma (ATL). The downregulation of NDRG2 expression is involved in tumour progression through the aberrant phosphorylation of several important signalling molecules. We observed that the downregulation of NDRG2 induced the translocation of protein arginine methyltransferase 5 (PRMT5) from the nucleus to the cytoplasm via the increased phosphorylation of PRMT5 at Serine 335. In NDRG2^low ATL, cytoplasmic PRMT5 enhanced HSP90A chaperone activity via arginine methylation, leading to tumour progression and the maintenance of oncogenic client proteins. Therefore, we examined whether the inhibition of PRMT5 activity is a drug target in NDRG2^low tumours. The knockdown of PRMT5 and binding partner methylsome protein 50 (MEP50) expression significantly demonstrated the suppression of cell proliferation via the degradation of AKT and NEMO in NDRG2^low ATL cells, whereas NDRG2-expressing cells did not impair the stability of client proteins. We suggest that the relationship between PRMT5/MEP50 and the downregulation of NDRG2 may exhibit a novel vulnerability and a therapeutic target. Treatment with the PRMT5-specific inhibitors CMP5 and HLCL61 was more sensitive in NDRG2^low cancer cells than in NDRG2-expressing cells via the inhibition of HSP90 arginine methylation, along with the degradation of client proteins. Thus, interference with PRMT5 activity has become a feasible and effective strategy for promoting cancer vulnerability in NDRG2^low ATL. Full article