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PubMed2026

Multi-omics and experimental validation identify RAPGEF2 as a protective prognostic biomarker in clear cell renal cell carcinoma.

Kidney Renal Clear Cell Carcinoma (KIRC) is characterized by marked molecular heterogeneity and metabolic reprogramming, underscoring the need for reliable biomarkers for prognostic assessment and individualized treatment. RAPGEF2, a guanine nucleotide exchange factor has been implicated in cell adhesion and differentiation, but its role in KIRC remains unclear. In this study, we systematically evaluated the expression pattern, prognostic significance, genomic associations, biological function, and therapeutic relevance of RAPGEF2 in KIRC through integrated multi-omics analyses and experimental validation. Pan-cancer single-cell and Spatial transcriptomic analysis revealed heterogeneous RAPGEF2 expression across tumor types, with a relatively prominent signal in KIRC, where RAPGEF2 was mainly enriched in endothelial cells. Survival analyses in the TCGA-KIRC showed that high RAPGEF2 expression was significantly associated with favorable overall survival, disease-specific survival, and progression-free interval, and these findings were validated in independent ICGC_RECA-EU and E-MTAB-1980 cohorts. Multivariate Cox regression further confirmed RAPGEF2 as an independent protective prognostic factor. Immunohistochemistry in a tissue microarray cohort demonstrated that higher RAPGEF2 protein expression was associated with improved overall survival. Genomic analyses showed that low RAPGEF2 expression was related to higher mutational burden. Functional assays demonstrated that RAPGEF2 knockdown promoted KIRC progression. Enrichment analyses indicated that RAPGEF2 may be associated with metabolic pathway remodeling, while immunotherapy cohort analyses suggested its potential association with therapeutic benefit. Collectively, RAPGEF2 is identified as a protective prognostic biomarker and potential functional regulator in KIRC.

Biomarker↗

PubMed2026

Pan-cancer analysis identifies GPRIN1 as a prognostic biomarker and promoter of cell proliferation in pancreatic cancer.

BACKGROUND: G protein-regulated inducer of neurite outgrowth 1 (GPRIN1), an emerging modulator of GPCR signaling, has been implicated in oncogenesis. However, its comprehensive role across human cancers, particularly in reshaping the tumor microenvironment (TME), remains poorly characterized. We aimed to elucidate the pan-cancer significance of GPRIN1 in TME modulation and its therapeutic implications. METHODS: We analyzed multi-omics data from TCGA and other public databases, performing a systematic analysis of GPRIN1 regarding expression, prognosis, immune infiltration, and genomic instability across 33 cancer types. To validate these bioinformatic findings, we performed lentiviral shRNA-mediated knockdown in pancreatic (PANC-1) and hepatic (HepG2) cancer cells to assess proliferation and migration. Crucially, the clinical relevance of GPRIN1 was further validated in an independent cohort of pancreatic cancer patients (N = 17) using immunohistochemistry (IHC). RESULTS: The analysis identified a lineage-dependent expression pattern. Epithelial tumors exhibited upregulation, whereas glioblastoma samples displayed downregulation. GPRIN1 expression consistently correlated with immune subtypes and CD8+ T cell abundance. In vitro assays demonstrated that GPRIN1 depletion significantly inhibited cell proliferation and migration (P < 0.0001). In the clinical validation cohort, multivariate Cox regression analysis identified high GPRIN1 protein levels as an independent predictor of post-operative recurrence. These patients also showed a trend toward extended overall survival. CONCLUSIONS: These findings define GPRIN1 as a context-dependent regulator of the TME. By integrating computational and experimental data, this study supports GPRIN1 as a potential biomarker for risk assessment in pancreatic cancer.

Humans↗

PubMed2026

Intratumoral collagen correlates with histological grade and patient prognosis in breast cancer.

Histological grading, using the Nottingham Grading System (NGS), is a major prognostic indicator for breast cancer. NGS involves the scoring of cancer cell-related morphological features, yet it overlooks tumor microenvironment (TME) components such as collagen. Collagen proteins, integral to the extracellular matrix (ECM), influence tumor architecture and progression but their relationship with histological grade is not fully characterized. Here, we assessed intratumoral collagen deposition using Masson Trichrome staining of whole slides (n = 166), proteomic profiling (n = 2) and transcriptomic analyses of the METABRIC (n = 1827) and TCGA-BRCA (n = 753) cohorts. We showed that low-grade tumors display significantly higher intratumoral collagen deposition compared to high-grade tumors. Moreover, we demonstrated that collagen expression at the transcript and protein levels (Masson Trichrome) could discriminate Grade II carcinomas into distinct prognostic groups, in which patients with Grade II carcinomas with elevated levels of collagen expression were associated with lower pTNM stage and better survival outcomes. Our results support the inclusion of TME features, such as collagen deposition, to enhance prognostic accuracy in breast cancer.

Humans↗

PubMed2026

Charting host structural variations in cervical cancer by long-read sequencing pinpoints a functional deletion in PIAS1.

Host structural variations (SVs) are critical in cancer development but their landscape and interaction with HPV integration in cervical carcinogenesis remain unclear. In this study, we performed Nanopore long-read sequencing on five HPV-positive cervical cancer tissues and two cell lines to profile host SVs. We identified thousands of SVs and statistically demonstrated their significant enrichment in genomic windows ±25 to ±50 kb from HPV integration sites. Cross-sample analysis revealed 60 shared SVs, including a recurrent deletion within the PIAS1 gene. Multi-omics integration (Hi-C, H3K27ac ChIP-seq, and TCGA data) showed that this deletion is associated with reduced PIAS1 expression, disruption of local topologically associating domains, advanced pathological tumor stage, and poorer overall survival. Functional assays confirmed that PIAS1 deficiency inhibits cervical cancer cell proliferation and migration. Our findings identify a PIAS1 deletion as a candidate driver event, and underscore the pivotal role of host genomic instability in HPV-associated oncogenesis.

Cervical cancer↗

PubMed2006

Diversity of the CYP21A2 gene: a 6.2-kb TaqI fragment and a 3.2-kb TaqI fragment mistaken as CYP21A1P.

The 3.7- and 3.2-kb fragments produced by TaqI digestion are respective crucial markers of the CYP21A2 and CYP21A1P genes for the analysis of the RCCX module in chromosome 6p21.3. Herein, we report two distinct CYP21A2 haplotypes. One occurred in a CAH patient with a 6.2-kb TaqI fragment caused by a mutation at the TaqI site (TCGA) located downstream of the CYP21A2 gene, and the other was a parent in a suspected CAH family with a 3.2-kb TaqI fragment resulting from a 156-bp fragment conversion of the CYP21P promoter sequence which led to the production of a TaqI site at nt -209 and two additional CYP21A1P nucleotides at nt -198 (C>T) and -188/-189 (T insertion). From further sequencing analysis, the promoter region of the 3.2-kb allele showed four normal transcriptional sequences positioned at nt -126C, -113G, -110T, and -103A. However, other nucleotides such as at nt -294T, -293A, and -282A were unchanged. We concluded that the 6.2-kb TaqI fragments of the CYP21A2 haplotype may lead to an incorrect result in the analysis between CYP21A2 and CYP21A1P. The formation of the 3.2-kb TaqI fragment allele which can be mistaken for the CYP21A1P gene may be caused by small-scale conversions of the CYP21A1P gene located between nt -126C and -282A. Therefore, the CYP21A2 haplotype not only presents a 3.7-kb TaqI fragment but also may possibly exist in multiple forms including both 6.2- and 3.2-kb fragments.

Adrenal Hyperplasia, Congenital↗

PubMed1991

Optically detected triplet-state magnetic resonance studies of the DNA complexes of the bisquinoline analogue of echinomycin.

The polymeric DNA and model duplex oligonucleotide complexes of the bisquinoline analogue of echinomycin (2QN) have been studied by optical detection of triplet-state magnetic resonance (ODMR) spectroscopy, with the quinoline chromophores of the drug used as intrinsic probes. Plots of ODMR transition frequencies versus monitored wavelength revealed heterogeneity in the phosphorescence emission of 2QN which was ascribed to the presence of a major and minor conformation of the drug in aqueous solutions (referred to as the red and blue forms of 2QN, respectively, in this report). ODMR results, in conjunction with findings from low-temperature phosphorescence investigations, indicate that the quinoline chromophores of the major (red) form of 2QN are involved in aromatic stacking interactions in complexes with the natural DNAs from Escherichia coli, Micrococcus lysodeikticus, Clostridium perfringens, and calf thymus as evidenced by red shifts in the phosphorescence 0,0-band of the drug, reductions in the phosphorescence lifetime and zero-field splitting (zfs) D and E parameters, and polarity reversals of the ODMR slow passage signals upon complex formation between the analogue and DNA. The polarity reversals, which reflect shifts in the triplet-state sublevel populations induced by complex formation, apparently result from changes in the triplet sublevel decay constants upon binding to the natural DNAs. The 2QN complexes of the double-stranded alternating copolymers poly(dG-dC).poly(dG-dC) [abbreviated as poly[d(G-C)2]] and poly(dA-dT).poly(dA-dT) [abbreviated as poly(dA-dT).poly(dA-dT) [abbreviated as poly[d(A-T)2], the homopolymer duplexes poly(dG).poly(dC) [abbreviated as poly(dG.dC)] and poly(dA).poly(dT) [abbreviated as poly(dA.dT)], and the self-complementary oligonucleotides d(ACGT)2, d(TCGA)2, and d(ACGTACGT)2 were also investigated. The extent of reduction of the zfs D parameter (delta D) for the major form of 2QN upon complex formation with the polymeric DNAs was found to scale linearly with the standard free energy of the drug-DNA interaction (delta G degrees) calculated from previously reported binding studies for these targets [Fox, K. R., et al. (1980) Biochem. J. 191, 729-740]. This relationship between spectroscopic and thermodynamic properties of the 2QN-polynucleotide complexes is a consequence of the effects of base stacking interactions on the electronic states of the intercalator, which were postulated to arise from second-order shifts of the ground-state and the triplet-state energies of the complex on the basis of a modification of the solvent effect theory of van Egmond et al. [(1975) Chem. Phys. Lett. 34, 423-426].

Animals↗

PubMed1994

Oligonucleotide studies of sequence-specific binding of chromomycin A3 to DNA.

Systematic kinetic, equilibrium binding, melting, and electrophoretic studies were carried out with oligonucleotides to determine the sequence specificities of chromomycin A3 (CHR) binding to DNA at the self-complementary tetranucleotide level. Decamers of the forms d(GTA-XGCY-TAC) and d(GTA-XCGY-TAC), with X, Y = A, G, C, or T, were used for this purpose. Results indicate that the binding preferences for CHR are in the order -GGCC- > -CGCG- > -GCGC-, -CCGG- > -AGCT- > -ACGT-, -TGCA- > -TCGA-. Detergent-induced drug dissociation studies revealed that CHR dissociates very slowly from both -GGCC- and -CGCG- sequences, with the former being measurably slower than the latter which in turn is at least an order of magnitude slower than the rest of the sequences. Thermal denaturation measurements indicate that the binding of CHR stabilizes the DNA duplex, with -GGCC- and -CGCG- exhibiting the largest effects. Results of gel electrophoretic retardation experiments support our general findings on the relative binding order. Our experimental results support earlier NMR findings by other researchers implicating the preference of aureolic acid drugs at the 5'GC3' step and further reveal significant modulations by the adjacent base pairs. Attempts were made to rationalize our results with the known detailed structural information from NMR studies.

Base Sequence↗

PubMed1991

Effects of the antitumor antibiotic mithramycin on the structure of repetitive DNA regions adjacent to its GC-rich binding site.

Regions of An.Tn, (GA)n.(TC)n, and (GT)n.(AC)n have been cloned into the SmaI (CCC/GGG) site of plasmid pUC19. HindIII-EcoRI restriction fragments containing these inserts have been used as substrates for footprinting experiments using DNase I, DNase II, and micrococcal nuclease as probes. These present good mithramycin binding sites (GGG) flanking repetitive regions to which the drug does not bind. In each case, mithramycin footprints are observed at the CCC/GGG sites, which are not affected by the nature of the surrounding sequences. Some weaker binding is detected at TCGA and ACCA sites and at regions of alternating GA. No binding is found to regions of alternating GT. An.Tn inserts (n = 23 or 69) are normally resistant to cleavage by all these probes; in the presence of mithramycin, a dramatic increase in DNase I cleavage is observed throughout the entire insert and is indicative of an alteration in DNA structure. Similar changes are seen with DNase II and micrococcal nuclease. These changes cannot be explained by invoking changes in the ratio of free substrate to cleavage agent. In contrast, cleavage of (GA)n.(CT)n and (GT)n.(AC)n inserts is not affected by drug binding. The results are consistent with a model in which mithramycin causes dramatic changes in the width of the DNA minor groove, generating a structure which has some properties of A-DNA, and suggest that this can be propagated into surrounding DNA regions in a sequence-dependent manner. The structural alterations with An.Tn are highly cooperative and can be transmitted over at least three turns of the DNA helix.

Base Composition↗

PubMed1990

Sequence preferences of DNA interstrand cross-linking agents: dG-to-dG cross-linking at 5'-CG by structurally simplified analogues of mitomycin C.

The nucleotide sequence preferences of the DNA interstrand cross-linking agents dehydroretronecine diacetate (DHRA), 2,3-bis(acetoxymethyl)-1-methylpyrrole (BAMP), dehydromonocrotaline, and dehydroretrorsine were studied by using synthetic DNA duplex fragments and polyacrylamide gel electrophoresis (PAGE). These agents have structural features in common with the reductively activated aziridinomitosene of mitomycin C (MC). Like MC, they preferentially cross-linked DNA duplexes containing the duplex sequence 5'-CG. For DHRA and BAMP interstrand cross-linked DNA duplexes, PAGE analysis of iron(II)-EDTA fragmentation reactions revealed the interstrand cross-links to be deoxyguanosine to deoxyguanosine (dG-to-dG), again analogous to DNA cross-links caused by MC. Unlike MC, DHRA could be shown to dG-to-dG cross-link a 5'-GC sequence. Furthermore, the impact of flanking sequence on the efficiency of interstrand cross-linking at 5'-CG was reduced for BAMP, with 5'-TCGA and 5'-GCGC being equally efficiently cross-linked. Possible origins of the 5'-CG sequence recognition common to all of the agents are discussed. A model is presented in which the transition state for the conversion of monoadducts to cross-links more closely resembles ground-state DNA at 5'-CG sequences.

Base Sequence↗

PubMed2002

Multimerization of restriction fragments by magnesium-mediated stable base pairing between overhangs: a cause of electrophoretic mobility shift.

The electrophoretic mobility shift assay (EMSA) or simply the "gel shift assay" is one of the most sensitive methods for studying the ability of a protein to bind to DNA. EMSAs are also widely used to investigate protein- or sequence-dependent DNA bending. Here we report that electrophoresis using physiological concentrations of Mg(2+) can cause a mobility shift of restriction fragments in nondenaturing polyacrylamide gels as the overhangs form stable base pairs. This phenomenon was observed at even 37 degrees C. The retardation was, however, more pronounced at low temperatures, where a three-nucleotide overhang 5'-GAC also caused a mobility shift. The stability of the pairing was generally high when the overhangs of four nucleotides display high GC content, while the mobility shift caused by 5'-AATT was greater than those caused by 5'-GATC, 5'-TCGA, and 5'-CTAG. This observation should be taken into account to avoid misinterpretation of the data when the EMSA, especially the circular permutation gel mobility shift assay, is performed using a running buffer that contains Mg(2+) ions. The stable adhesion between short overhangs may present an important basis for genome stability and many genetic processes occurring in living cells.

Base Pairing↗

PubMed1996

Cooperativity in the binding of echinomycin to DNA fragments containing closely spaced CpG sites.

Quantitative footprinting has been used to investigate cooperative binding of the antitumor antibiotic echinomycin to DNA fragments containing closely spaced CpG steps. The sequences of the designed DNA fragments contained two pairs of strong echinomycin binding sites: a pair of ACGT sites together with an ACGT site and a TCGA site, either directly adjacent or separated by two or four A.T base pairs. The results demonstrate that the binding of echinomycin to the sequences ACGTACGT and TCGAACGT is highly cooperative. The extent of cooperativity depends on the nature of the sequences clamped by the antibiotic and diminishes as the distance between the binding sites is increased. Various methods of extracting the information necessary to establish cooperativity have been compared. Beyond the specific interest in echinomycin-DNA interaction, the present quantitative footprinting study provides a model that may be generally applicable for designing investigations into cooperativity in drug-DNA recognition.

Antibiotics, Antineoplastic↗

PubMed1996

Dissociation kinetics of echinomycin from CpG binding sites in different sequence environments.

We have examined the kinetics of dissociation of echinomycin from CpG sites in several DNA fragments containing synthetic DNA inserts by a variation of the footprinting technique. Complexes of the ligand with radiolabeled DNA fragments were dissociated by adding an excess of unlabeled calf thymus DNA. Samples were removed from this mixture at subsequent time intervals and subjected to DNase I footprinting. The rate of disappearance of the footprints varied considerably between the various CpG sites. At 20 degrees C, echinomycin dissociates more slowly from CpG sites flanked by (AT)n (t1/2 approximately 40 min) and (CA)n.(TG)n (t1/2 approximately 11 min) than by An.Tn (t1/2 < 3 min). In each sequence context the dissociation from ACGT is slower than that from TCGA. (TAA)4CG(TTA)4 also represents a very good binding site (t1/2 approximately 35 min), which is less sensitive to changes in temperature than most other sites. Within sequences (AT)10(G/C)4(AT)10, the dissociation from CGGC is slower than that from CCCG or CCGC.

Antibiotics, Antineoplastic↗

PubMed1999

Functional roles of the conserved aromatic amino acid residues at position 108 (motif IV) and position 196 (motif VIII) in base flipping and catalysis by the N6-adenine DNA methyltransferase from Thermus aquaticus.

The DNA methyltransferase (Mtase) from Thermus aquaticus (M.TaqI) catalyzes the transfer of the activated methyl group of S-adenosyl-L-methionine to the N6 position of adenine within the double-stranded DNA sequence 5'-TCGA-3'. To achieve catalysis M.TaqI flips the target adenine out of the DNA helix. On the basis of the three-dimensional structure of M.TaqI in complex with the cofactor and its structural homology to the C5-cytosine DNA Mtase from Haemophilus haemolyticus, Tyr 108 and Phe 196 were suggested to interact with the extrahelical adenine. The functional roles of these two aromatic amino acid residues in M.TaqI were investigated by mutational analysis. The obtained mutant Mtases were analyzed in an improved kinetic assay, and their ability to flip the target base was studied in a fluorescence-based assay using a duplex oligodeoxynucleotide containing the fluorescent base analogue 2-aminopurine at the target position. While the mutant Mtases containing the aromatic amino acid Trp at position 108 or 196 (Y108W and F196W) showed almost wild-type catalytic activity, the mutant Mtases with the nonaromatic amino acid Ala (Y108A and F196A) had a strongly reduced catalytic constant. Y108A was still able to flip the target base, whereas F196A was strongly impaired in base flipping. These results indicate that Phe 196 is important for stabilizing the extrahelical target adenine and suggest that Tyr 108 is involved in placing the extrahelical target base in an optimal position for methyl group transfer. Since both aromatic amino acids belong to the conserved motifs IV and XIII found in N6-adenine and N4-cytosine DNA Mtases as well as in N6-adenine RNA Mtases, a similar function of aromatic amino acid residues within these motifs is expected for the different Mtases.

Amino Acid Sequence↗

PubMed2003

Design of a new fluorescent cofactor for DNA methyltransferases and sequence-specific labeling of DNA.

Sequence-specific labeling of DNA is of immense interest for analytical and functional studies of DNA. We present a novel approach for sequence-specific labeling of DNA using a newly designed fluorescent cofactor for the DNA methyltransferase from Thermus aquaticus (M.TaqI). Naturally, M.TaqI catalyzes the nucleophilic attack of the exocyclic amino group of adenine within the double-stranded 5'-TCGA-3' DNA sequence onto the methyl group of the cofactor S-adenosyl-L-methionine (AdoMet) leading to methyl group transfer. The design of a new fluorescent cofactor for covalent labeling of DNA was based on three criteria: (1) Replacement of the methionine side chain of the natural cofactor AdoMet by an aziridinyl residue leads to M.TaqI-catalyzed nucleophilic ring opening and coupling of the whole nucleoside to DNA. (2) The adenosyl moiety is the molecular anchor for cofactor binding. (3) Attachment of a fluorophore via a flexible linker to the 8-position of the adenosyl moiety does not block cofactor binding. According to these criteria the new fluorescent cofactor 8-amino[1''-(N''-dansyl)-4''-aminobutyl]-5'-(1-aziridinyl)-5'-deoxyadenosine (3) was synthesized. 3 binds about 4-fold better than the natural cofactor AdoMet to M.TaqI and is coupled with a short duplex oligodeoxynucleotide by M.TaqI. The identity of the expected modified nucleoside was verified by electrospray ionization mass spectrometry after enzymatic fragmentation of the product duplex. In addition, the new cofactor 3 was used to sequence-specifically label plasmid DNA in a M.TaqI-catalyzed reaction.

Aziridines↗

PubMed2001

Structure of the N6-adenine DNA methyltransferase M.TaqI in complex with DNA and a cofactor analog.

The 2.0 A crystal structure of the N6-adenine DNA methyltransferase M.TaqI in complex with specific DNA and a nonreactive cofactor analog reveals a previously unrecognized stabilization of the extrahelical target base. To catalyze the transfer of the methyl group from the cofactor S-adenosyl-l-methionine to the 6-amino group of adenine within the double-stranded DNA sequence 5'-TCGA-3', the target nucleoside is rotated out of the DNA helix. Stabilization of the extrahelical conformation is achieved by DNA compression perpendicular to the DNA helix axis at the target base pair position and relocation of the partner base thymine in an interstrand pi-stacked position, where it would sterically overlap with an innerhelical target adenine. The extrahelical target adenine is specifically recognized in the active site, and the 6-amino group of adenine donates two hydrogen bonds to Asn 105 and Pro 106, which both belong to the conserved catalytic motif IV of N6-adenine DNA methyltransferases. These hydrogen bonds appear to increase the partial negative charge of the N6 atom of adenine and activate it for direct nucleophilic attack on the methyl group of the cofactor.

Adenine↗

PubMed2026

FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by profound immunosuppression that facilitates tumor progression and promotes therapeutic resistance. Fibroblast activation protein (FAP), a recognized theranostic target in multiple cancers, is upregulated in GBM and predominantly expressed by pericyte-like stromal cells. Here we identify a role for FAP⁺ pericyte-like cells in shaping the GBM immune microenvironment through monocyte recruitment and differentiation. Analysis of The Cancer Genome Atlas (TCGA) datasets, supported by reverse-transcription quantitative PCR and immunohistochemistry, revealed that elevated FAP expression-serving as a proxy for the abundance of FAP⁺ pericyte-like cells-is associated with an immune-enriched tumor microenvironment characterized by higher macrophage abundance and elevated expression of M2 polarization markers. Spatial analyses, including immunofluorescence and spatial transcriptomics, demonstrated that immunosuppressive macrophages preferentially localize in proximity to FAP⁺ pericytes. Single-cell RNA sequencing identified these FAP⁺ cells as a distinct perivascular stromal subset with a unique expression pattern of extracellular matrix components and cytokines, including CCL2 and CSF1, with corresponding receptors expressed on myeloid cells. Functional assays using patient-derived FAP⁺ pericyte-like cells confirmed their ability to attract monocytes via soluble mediators and to promote their differentiation and polarization into tumor-associated macrophages with immunoregulatory features, partly mediated by the CSF1-CSF1R axis. Orthotopic co-implantation experiments in mice further supported their capacity to enhance myeloid infiltration in vivo. Consistent with these biological effects, a transcriptional signature characteristic of FAP⁺ pericytes correlated with worse overall survival in patients with GBM. Together, these findings position FAP⁺ pericyte-like cells as modulators of the GBM immune landscape, fostering a tumor-permissive niche by promoting the differentiation of circulating monocytes into immunoregulatory macrophages. Targeting this stromal population may offer new therapeutic avenues to reprogram tumor-associated immune responses in GBM.

Journal Article↗

PubMed2025

The involvement of lncRNA EMSLR in the disulfidptosis and progression of endometrial carcinoma.

The incidence of endometrial cancer (EC) continues to rise. Disulfidptosis, a novel form of cell death, may represent a potential therapeutic target in EC. Through bioinformatic analysis of The Cancer Genome Atlas (TCGA) database, E2F1 mRNA-stabilizing lncRNA (EMSLR) was identified as a lncRNA related to disulfidptosis in EC. Functional assays, including cell proliferation and xenograft assays, demonstrated that knockdown of EMSLR significantly impeded EC cell proliferation, whereas overexpression of EMSLR promoted cell viability. Additionally, EMSLR was found to be associated with glucose uptake and NADPH production in glucose-restricted culture conditions. Moreover, downregulation of EMSLR markedly increased cell death and induced cytoskeletal collapse under glucose deprivation, as evidenced by F-actin and cell death staining. Notably, we observed a strong correlation between EMSLR and the c-MYC-GLUT1 pathway. Mechanistically, EMSLR was found to mediate the expression and nuclear translocation of c-MYC, thereby regulating the progression of EC and its associated disulfidptosis. In conclusion, EMSLR is identified as a disulfidptosis-related gene in endometrial cancer. Elucidating the function and molecular mechanisms of EMSLR in EC presents a promising avenue for therapeutic intervention in patients.

Female↗

PubMed2025

Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival.

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.

Humans↗