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PubMed2002

The Arabidopsis gene PEPINO/PASTICCINO2 is required for proliferation control of meristematic and non-meristematic cells and encodes a putative anti-phosphatase.

Growth in organisms requires that cell division versus differentiation are precisely controlled and that cells, once differentiated, do not resume proliferation activity. Mutants of the Arabidopsis gene PEPINO/PASTICCINO2 develop abnormal shoot phenotypes from slow tumour-like cell proliferation. Abnormal proliferation is enhanced in a mutant background, which elevates endogenous cytokinin levels as seen in double mutants of pepino and altered meristem primordia1. The enlarged shoot apical meristem produces supernumerary abnormal leaves. However, comparison of expression patterns of Cyclin1At and the homeobox gene KNAT2 indicates that PEPINO ( PEP) is involved in cell cycle regulation of meristematic and non-meristematic cells. PEP encodes a putative anti-phosphatase, a representative of an enigmatic class of proteins, which might participate in proliferation processes. In mammals at least two proteins, Sbf1 and STYX, have been predicted to represent functional anti-phosphatases controlling cell proliferation. However, the in vivo function of this class of molecules is not known since no loss-of-function mutants have been reported to date. Anti-phosphatases display a natural change of the essential cysteine by glycine in the phosphatase catalytic signature motif HCxxGxxR(S/T). The remaining motif harbours highly conserved amino acid residues and is thought to constitute a pocket that enables such proteins to bind but not catalyse phosphorylated residues. One of the sequenced mutations in PEP indicates that the integrity of this anti-phosphatase signature motif is essential for function. The analysis of pepino, the first known loss-of-function mutant of an anti-phosphatase in a multicellular organism, proves the biological significance of these molecules.

Amino Acid Sequence↗

PubMed1998

On error minimization in a sequential origin of the standard genetic code.

Distances between amino acids were derived from the polar requirement measure of amino acid polarity and Benner and co-workers' (1994) 74-100 PAM matrix. These distances were used to examine the average effects of amino acid substitutions due to single-base errors in the standard genetic code and equally degenerate randomized variants of the standard code. Second-position transitions conserved all distances on average, an order of magnitude more than did second-position transversions. In contrast, first-position transitions and transversions were about equally conservative. In comparison with randomized codes, second-position transitions in the standard code significantly conserved mean square differences in polar requirement and mean Benner matrix-based distances, but mean absolute value differences in polar requirement were not significantly conserved. The discrepancy suggests that these commonly used distance measures may be insufficient for strict hypothesis testing without more information. The translational consequences of single-base errors were then examined in different codon contexts, and similarities between these contexts explored with a hierarchical cluster analysis. In one cluster of codon contexts corresponding to the RNY and GNR codons, second-position transversions between C and G and transitions between C and U were most conservative of both polar requirement and the matrix-based distance. In another cluster of codon contexts, second-position transitions between A and G were most conservative. Despite the claims of previous authors to the contrary, it is shown theoretically that the standard code may have been shaped by position-invariant forces such as mutation and base content. These forces may have left heterogeneous signatures in the code because of differences in translational fidelity by codon position. A scenario for the origin of the code is presented wherein selection for error minimization could have occurred multiple times in disjoint parts of the code through a phyletic process of competition between lineages. This process permits error minimization without the disruption of previously useful messages, and does not predict that the code is optimally error-minimizing with respect to modern error. Instead, the code may be a record of genetic process and patterns of mutation before the radiation of modern organisms and organelles.

Amino Acids↗

PubMed2000

FYVE-DSP1, a dual-specificity protein phosphatase containing an FYVE domain.

Dual-specificity protein phosphatases (DSPs) dephosphorylate proteins at Ser/Thr and Tyr. FYVE domain is a double zinc finger motif which specifically binds phosphatidylinositol(3)-phosphate. Here, we report a novel dual specificity phosphatase that contains a FYVE domain at the C-terminus. We designate the protein FYVE-DSP1. Molecular cloning yielded three isoforms of the enzyme presumably derived from alternate RNA splicing. Sequence alignment revealed that the catalytic phosphatase domain of FYVE-DSP1 closely resembled that of myotubularin, while its FYVE domain has all the conserved amino acid residues found in other proteins of the same family. Recombinant FYVE-DSP1 is partitioned in both cytosolic and membrane fractions. It dephosphorylates proteins phosphorylated on Ser, Thr, and Tyr residues and low molecular weight phosphatase substrate para-nitrophenylphosphate. It shows typical characteristics of other DSPs and protein tyrosine phosphatases (PTPs). These include inhibition by sodium vanadate and pervanadate, pH dependency, and inactivation by mutation of the key cysteinyl residue at the phosphatase signature motif. Finally, PCR analyses demonstrated that FYVE-DSP1 is widely distributed in human tissues but different spliced forms expressed differently.

Alternative Splicing↗

PubMed2004

Importance of conserved acidic residues in mntH, the Nramp homolog of Escherichia coli.

A bioinformatic approach was used for the identification of residues that are conserved within the Nramp family of metal transporters. Site-directed mutagenesis was then carried out to change six conserved acidic residues (i.e., Asp-34, Glu-102, Asp-109, Glu-112, Glu-154, and Asp-238) in the E. coli Nramp homolog mntH. Of these six, five of them, Asp-34, Glu-102, Asp-109, Glu-112, and Asp-238 appear to be important for function since conservative substitutions at these sites result in a substantial loss of transport function. In addition, all of the residues within the signature sequence of the Nramp family, DPGN, were also mutated in this study. Each residue was changed to several different side chains, and of ten site-directed mutations made in this motif, only P35G showed any measurable level of (54)Mn(2+) uptake with a V(max) value of approximately 10% of wild-type and a slightly elevated K(m) value. Overall, the data are consistent with a model where helix breakers in the conserved DPGN motif in TMS-1 provide a binding pocket in which Asp-34, Asn-37, Asp-109, Glu-112 (and possibly other residues) are involved in the coordination of Mn(2+). Other residues such as Glu-102 and Asp238 may play a role in the release of Mn(2+) to the cytoplasm or may be involved in maintaining secondary structure.

Amino Acid Motifs↗

PubMed2002

Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis.

Ink4a/Arf inactivation and epidermal growth factor receptor (EGFR) activation are signature lesions in high-grade gliomas. How these mutations mediate the biological features of these tumors is poorly understood. Here, we demonstrate that combined loss of p16(INK4a) and p19(ARF), but not of p53, p16(INK4a), or p19(ARF), enables astrocyte dedifferentiation in response to EGFR activation. Moreover, transduction of Ink4a/Arf(-/-) neural stem cells (NSCs) or astrocytes with constitutively active EGFR induces a common high-grade glioma phenotype. These findings identify NSCs and astrocytes as equally permissive compartments for gliomagenesis and provide evidence that p16(INK4a) and p19(ARF) synergize to maintain terminal astrocyte differentiation. These data support the view that dysregulation of specific genetic pathways, rather than cell-of-origin, dictates the emergence and phenotype of high-grade gliomas.

Animals↗

PubMed2004

MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias.

Little is known about the expression levels or function of micro-RNAs (miRNAs) in normal and neoplastic cells, although it is becoming clear that miRNAs play important roles in the regulation of gene expression during development [Ambros, V. (2003) Cell 113, 673-676; McManus, M. T. (2003) Semin. Cancer Biol. 13, 253-258]. We now report the genomewide expression profiling of miRNAs in human B cell chronic lymphocytic leukemia (CLL) by using a microarray containing hundreds of human precursor and mature miRNA oligonucleotide probes. This approach allowed us to identify significant differences in miRNome expression between CLL samples and normal CD5+ B cells; data were confirmed by Northern blot analyses and real-time RT-PCR. At least two distinct clusters of CLL samples can be identified that were associated with the presence or absence of Zap-70 expression, a predictor of early disease progression. Two miRNA signatures were associated with the presence or absence of mutations in the expressed Ig variableregion genes or with deletions at 13q14, respectively. These data suggest that miRNA expression patterns have relevance to the biological and clinical behavior of this leukemia.

B-Lymphocytes↗

PubMed2001

A three-dimensional model of the human facilitative glucose transporter Glut1.

The human facilitative transporter Glut1 is the major glucose transporter present in all human cells, has a central role in metabolism, and is an archetype of the superfamily of major protein facilitators. Here we describe a three-dimensional structure of Glut1 based on helical packing schemes proposed for lactose permease and Glut1 and predictions of secondary structure, and refined using energy minimization, molecular dynamics simulations, and quality and environmental scores. The Ramachandran scores and the stereochemical quality of the structure obtained were as good as those for the known structures of the KcsA K(+) channel and aquaporin 1. We found two channels in Glut1. One of them traverses the structure completely, and is lined by many residues known to be solvent-accessible. Since it is delimited by the QLS motif and by several well conserved residues, it may serve as the substrate transport pathway. To validate our structure, we determined the distance between these channels and all the residues for which mutations are known. From the locations of sugar transporter signatures, motifs, and residues important to the transport function, we find that this Glut1 structure is consistent with mutagenesis and biochemical studies. It also accounts for functional deficits in seven pathogenic mutants.

Algorithms↗

PubMed1997

GTP hydrolysis controls stringent selection of the AUG start codon during translation initiation in Saccharomyces cerevisiae.

We have isolated and characterized two suppressor genes, SUI4 and SUI5, that can initiate translation in the absence of an AUG start codon at the HIS4 locus in Saccharomyces cerevisiae. Both suppressor genes are dominant in diploid cells and lethal in haploid cells. The SUI4 suppressor gene is identical to the GCD11 gene, which encodes the gamma subunit of the eIF-2 complex and contains a mutation in the G2 motif, one of the four signature motifs that characterizes this subunit to be a G-protein. The SUI5 suppressor gene is identical to the TIF5 gene that encodes eIF-5, a translation initiation factor known to stimulate the hydrolysis of GTP bound to eIF-2 as part of the 43S preinitiation complex. Purified mutant eIF-5 is more active in stimulating GTP hydrolysis in vitro than wild-type eIF-5, suggesting that an alteration of the hydrolysis rate of GTP bound to the 43S preinitiation complex during ribosomal scanning allows translation initiation at a non-AUG codon. Purified mutant eIF-2gamma complex is defective in ternary complex formation and this defect correlates with a higher rate of dissociation from charged initiator-tRNA in the absence of GTP hydrolysis. Biochemical characterization of SUI3 suppressor alleles that encode mutant forms of the beta subunit of eIF-2 revealed that these mutant eIF-2 complexes have a higher intrinsic rate of GTP hydrolysis, which is eIF-5 independent. All of these biochemical defects result in initiation at a UUG codon at the his4 gene in yeast. These studies in light of other analyses indicate that GTP hydrolysis that leads to dissociation of eIF-2 x GDP from the initiator-tRNA in the 43S preinitiation complex serves as a checkpoint for a 3-bp codon/anticodon interaction between the AUG start codon and the initiator-tRNA during the ribosomal scanning process.

Amino Acid Sequence↗

PubMed2006

Transport of multidrug resistance substrates by the Streptococcus agalactiae hemolysin transporter.

Streptococcus agalactiae (group B streptococcus [GBS]) causes neonatal sepsis, pneumonia, and meningitis, as well as infections of the bovine udder. The S. agalactiae hemolysin is regarded as an important virulence factor, and hemolysin expression is dependent on the cyl gene cluster. cylA and cylB encode the ATP binding and transmembrane domains of a typical ATP binding cassette (ABC) transporter. The deduced proteins contain the signature sequence of a multidrug resistance (MDR) transporter, and mutation of the genes results in a nonhemolytic and nonpigmented phenotype. To further elucidate the function of the putative transporter, nonpolar deletion mutants of cylA were constructed. These mutants are nonhemolytic and can be complemented by the transporter genes. Wild-type strain and nonhemolytic cylA and cylK deletion mutants were exposed to known substrates of MDR transporters. Mutation of cylA significantly impaired growth in the presence of daunorubicin, doxorubicin, and rhodamine 6G and resulted in a decreased export of doxorubicin from the cells. The mutation of cylK, a gene of unknown function located downstream from cylA, caused a loss of hemolysis but had no effect on the transport of MDR substrates. Furthermore, the hemolytic activity of the wild-type strain was inhibited by reserpine in a dose-dependent manner. We conclude that CylAB closely resembles an ABC-type MDR transporter and propose that the GBS hemolysin molecule represents a natural substrate of the transporter.

Anti-Bacterial Agents↗

PubMed2004

Phylogenetic relationships among marine Alteromonas-like proteobacteria: emended description of the family Alteromonadaceae and proposal of Pseudoalteromonadaceae fam. nov., Colwelliaceae fam. nov., Shewanellaceae fam. nov., Moritellaceae fam. nov., Ferrimonadaceae fam. nov., Idiomarinaceae fam. nov. and Psychromonadaceae fam. nov.

The phylogenetic relationships among marine Alteromonas-like bacteria of the genera Alteromonas, Pseudoalteromonas, Glaciecola, Thalassomonas, Colwellia, Idiomarina, Oceanimonas, Oceanisphaera, Shewanella, Moritella, Ferrimonas, Psychromonas and several other genera of the 'Gammaproteobacteria' were studied. Results of 16S rRNA gene sequence analyses revealed that some members of these genera formed several coherent groups at the family level. Characteristic signature oligonucleotides for studied taxa were defined. Signature positions are divided into three classes: (i) single compensatory mutations, (ii) double compensatory mutations and (iii) mutations affecting nucleotides not paired in the secondary structure. The 16S rRNA gene sequence similarity level within genera was 93 % or above. This value can be a useful additional criterion for genus discrimination. On the basis of this work and previous polyphasic taxonomic studies, the circumscription of the family Alteromonadaceae is limited to the genera Alteromonas and Glaciecola and the creation is proposed of the families Pseudoalteromonadaceae fam. nov. to accommodate bacteria of the genera Pseudoalteromonas and Algicola gen. nov. (formerly Pseudoalteromonas bacteriolytica) and Colwelliaceae fam. nov. to accommodate bacteria of the genera Colwellia and Thalassomonas. Bacteria of the genera Oceanimonas and Oceanisphaera formed a robust cluster and shared common signature oligonucleotides. Because of deep branching and lack of association with any other genus, the following families are proposed that include single genera: Idiomarinaceae fam. nov., Psychromonadaceae fam. nov., Moritellaceae fam. nov., Ferrimonadaceae fam. nov. and Shewanellaceae fam. nov. Finally, this study also revealed that [Hyphomicrobium] indicum should be reclassified as Photobacterium indicum comb. nov.

Alteromonas↗

PubMed2005

A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia.

BACKGROUND: MicroRNA expression profiles can be used to distinguish normal B cells from malignant B cells in patients with chronic lymphocytic leukemia (CLL). We investigated whether microRNA profiles are associated with known prognostic factors in CLL. METHODS: We evaluated the microRNA expression profiles of 94 samples of CLL cells for which the level of expression of 70-kD zeta-associated protein (ZAP-70), the mutational status of the rearranged immunoglobulin heavy-chain variable-region (IgV(H) ) gene, and the time from diagnosis to initial treatment were known. We also investigated the genomic sequence of 42 microRNA genes to identify abnormalities. RESULTS: A unique microRNA expression signature composed of 13 genes (of 190 analyzed) differentiated cases of CLL with low levels of ZAP-70 expression from those with high levels and cases with unmutated IgV(H) from those with mutated IgV(H) . The same microRNA signature was also associated with the presence or absence of disease progression. We also identified a germ-line mutation in the miR-16-1-miR-15a primary precursor, which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germ-line or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (P<0.001). CONCLUSIONS: A unique microRNA signature is associated with prognostic factors and disease progression in CLL. Mutations in microRNA transcripts are common and may have functional importance.

Disease Progression↗

PubMed2005

Transcriptional profiling and assessment of cell lines as in vitro models for mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive malignancy and new treatment modalities must be established to increase patient survival time. In the search for new therapeutic targets, reliable and well-characterised in vitro models are essential. In this study, we have characterised three MCL cell lines (SP53, Granta 519 and NCEB1) in comparison with primary tumours from MCL, follicular lymphomas (FL), a FL cell line (RL), a Burkitt lymphoma cell line (RAJI) and five different B cell populations from healthy individuals. Expression profiling was used to determine the relative expression of >12000 transcripts in these samples, and flow cytometry analysis was performed to establish a phenotypic signature for each of the cell lines. In addition, the cell lines were sequenced, and the frequency of somatic mutations and immunoglobulin (Ig) variable heavy chain (VH) usage were determined. We show by hierarchical clustering that the cell lines retain a genetic signature similar to primary MCL, which readily separated the MCL samples from the other lymphoma cell lines and the FL tumours. Furthermore, the MCL cell lines showed differences in the frequency of VH somatic mutations (0-2.1%). The increased number of mutations in NCEB1, compared to the other MCL cell lines, was in agreement with a decreased expression of CD31, CD44, CXCR5, CCR7 and CCR6. Taken together, our data show that the cell lines are clearly derived from MCL tumours and expressed similar genetic and phenotypic signatures compared to primary tumours, which confirmed their usefulness as in vitro models.

B-Lymphocytes↗

PubMed1999

Mutations in the yeast two pore K+ channel YKC1 identify functional differences between the pore domains.

The K+ channel of Saccharomyces cerevisiae encoded by the YKC1 gene includes two pore-loop sequences that are thought to form the hydrophilic lining of the pore. Gating of the channel is promoted by membrane depolarisation and is regulated by the extracellular K+ concentration ([K+]o) both in the yeast and when expressed in Xenopus oocytes. Our previous work showed that substitutions of equivalent residues L293 and A428 within the pore-loops had qualitatively similar effects on both the [K+]o-sensitivity of channel gating and its voltage-dependence. Here, we report that mutations of equivalent residues N275 and N410, N-terminal from the K+ channel signature sequences of the two pores, have very different actions on channel gating and, in this case, are without effect on its voltage-sensitivity. The mutation N410D slowed current activation in a [K+]o-dependent manner and it accelerated deactivation, but without significant effect on the apparent affinity for K+. The N275D mutant, by contrast, had little effect on the [K+]o-sensitivity for activation and it greatly altered the. [K+]o-dependence of current deactivation. Neither mutant affected the voltage-dependence of the steady-state current nor the ability for other alkali cations to substitute for K+ in regulating gating. The double mutant N410D-N275D showed characteristics of N410D in the [K+]o-sensitivity of current activation and of N275D in the [K+]o-sensitivity of deactivation, suggesting that little interaction occurs between pore domains with mutations at these sites. The results indicate that the two pore domains are not functionally equivalent and they suggest that the regulation of gating by external K+ is mediated by K+ binding at two physically distinct sites with different actions.

Animals↗

PubMed2001

Random mutagenesis-PCR to introduce alterations into defined DNA sequences for validation of SNP and mutation detection methods.

Sensitive and high throughput techniques are required for the detection of DNA sequence variants such as single nucleotide polymorphisms (SNPs) and mutations. One problem, common to all methods of SNP and mutation detection, is that experimental conditions required for detection of DNA sequence variants depend on the specific DNA sequence to be analyzed. Although algorithms and other calculations have been developed to predict the experimental conditions required to detect DNA sequence variation in a specific DNA sequence, these algorithms do not always provide reliable information and experimental conditions for SNP and mutation detection must be devised empirically. Determination of experimental conditions for detection of DNA sequence variation is difficult when samples containing only wild type sequence are available. When patient derived positive controls are used, increasingly there are valid concerns about commercial ownership and patient privacy. This report presents a rapid and efficient method, employing random mutagenesis-PCR (RM-PCR) using low fidelity DNA polymerase, to randomly introduce single and multiple base substitutions and deletions into DNA sequences of interest. Clones with sequence changes were used to validate denaturing HPLC (DHPLC) algorithm predictions, optimize conditions for mutation detection in exon 15 of the tyrosine kinase domain of the MET proto-oncogene, and to confirm the association between specific DNA sequence changes and unique DHPLC chromatographic profiles (signatures). Finally, DNA from 33 papillary renal carcinoma (PRC) patients was screened for mutations in exon 15 of MET using "validated" DHPLC conditions as a proof of principle application of RM-PCR. Use of RM-PCR for DHPLC and other SNP/mutation detection methods is discussed along with challenges associated with detecting sequence alterations in mixed tumor/normal tissue, pooled samples, and from regions of the genome that have been amplified during tumorigenesis or duplicated during evolution. Hum Mutat 17:210-219, 2001. Published 2001 Wiley-Liss, Inc.

Chromatography, High Pressure Liquid↗

PubMed2006

Evidence for overdominant selection maintaining X-linked fitness variation in Drosophila melanogaster.

The role of balancing selection in maintaining genetic variation for fitness is largely unresolved. This reflects the inherent difficulty in distinguishing between models of recurrent mutation versus selection, which produce similar patterns of inbreeding depression, as well as the limitations of testing such hypotheses when fitness variation is averaged across the genome. Signatures of X-linked overdominant selection are less likely to be obscured by mutational variation because X-linked mutations are rapidly eliminated by purifying selection in males. Although models maintaining genetic variation for fitness are not necessarily mutually exclusive, a series of predictions for identifying X-linked overdominant selection can be used to separate its contribution from other underlying processes. We consider the role of overdominant selection in maintaining fitness variation in a sample of 12 X chromosomes from a population of Drosophila melanogaster. Substantial variation was observed for male reproductive success and female fecundity, with heterozygous-X genotypes exhibiting the greatest degree of variance, a finding that agrees well with predictions of the overdominance model. The importance of X-linked overdominant selection is discussed along with models of recurrent mutation and sexually antagonistic selection.

Alleles↗

PubMed2003

Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia.

The SH2 domain-containing inositol 5'-phosphatase (SHIP) is crucial in hematopoietic development. To evaluate the possible tumor suppressor role of the SHIP gene in myeloid leukemogenesis, we examined primary leukemia cells from 30 acute myeloid leukemia (AML) patients, together with eight myeloid leukemia cell lines. A somatic mutation at codon 684, replacing Val with Glu, was detected in one patient, lying within the signature motif 2, which is the phosphatase active site. The results of an in vitro inositol 5'-phosphatase assay revealed that the mutation reduced catalytic activity of SHIP. Leukemia cells with the mutation showed enhanced Akt phosphorylation following IL-3 stimulation. K562 cells transfected with the mutated SHIP-V684E cDNA showed a growth advantage even at lower serum concentrations and resistance to apoptosis induced by serum deprivation and exposure to etoposide. These results suggest a possible role of the mutated SHIP gene in the development of acute leukemia and chemotherapy resistance through the deregulation of the phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3)/Akt signaling pathway. This is the first report of a mutation in the SHIP gene in any given human cancer, and indicates the need for more attention to be paid to this gene with respect to cancer pathogenesis.

Acute Disease↗

PubMed2005

Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis.

Splenic marginal zone lymphoma (SMZL) is a newly recognized lymphoma type whose precise molecular pathogenesis is still essentially unknown. This hampers differential diagnosis with other small B-cell malignancies. With the aim of characterizing this tumor more comprehensively, and of identifying new diagnostic and prognostic markers, we performed cDNA microarray expression profiling and tissue microarray (TMA) immunohistochemical studies in a relatively large series of 44 SMZLs. The results were related to immunoglobulin heavy chain variable region (IgV(H)) mutational status and clinical outcome. SMZLs display a largely homogenous signature, implying the existence of a single molecular entity. Of the genes deregulated in SMZLs, special mention may be made of the genes involved in B-cell receptor (BCR) signaling, tumor necrosis factor (TNF) signaling and nuclear factor-kappaB (NF-kappaB) activation, such as SYK, BTK, BIRC3, TRAF3, and LTB. Other genes observed were SELL and LPXN, which were highly expressed in spleen, and lymphoma oncogenes, such as ARHH and TCL1. In contrast, the genes CAV1, CAV2, and GNG11 located in 7q31, a commonly deleted area, were down-regulated in the entire series. A comparison with the genes comprising the signature of other small B-cell lymphomas identified 3 genes whose expression distinguishes SMZL, namely ILF1, SENATAXIN, and CD40. Shorter survival was associated with CD38 expression, naive IgV(H) genes, and the expression of a set of NF-kappaB pathway genes, including TRAF5, REL, and PKCA.

Biomarkers, Tumor↗

PubMed2026

An oxidative stress - and immunotherapy-related six-gene signature defines immune subtypes and predicts prognosis and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Oxidative stress and the tumor immune microenvironment jointly shape hepatocellular carcinoma (HCC) progression and response to immunotherapy, yet integrated biomarkers linking these processes are lacking. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify oxidative stress- and immunotherapyrelated differentially expressed genes (OSIRDEGs). Functional enrichment, weighted gene co-expression network analysis (WGCNA) and LASSO-Cox regression were used to construct a prognostic signature. Consensus clustering, TIDE, CIBERSORT and ssGSEA characterized immune phenotypes. Somatic mutation, copy-number and drug-response data were integrated to assess genomic alterations and drug sensitivity. Expression of model genes was validated by qRT-PCR and western blotting in HCC cell lines. RESULTS: We identified 24 OSIRDEGs enriched in cell-cycle and mitotic pathways. WGCNA intersection yielded 18 module genes, from which a six-gene signature (BUB1B, CDKN2A, CENPE, HMMR, PTTG1, SPP1) was derived. The signature robustly stratified patients into high- and low-risk groups with significantly different progression-free and disease-free survival in both TCGA-LIHC and GSE14520. Based on signature expression, two molecular subtypes were defined, exhibiting distinct survival, immune landscapes and predicted immunotherapy responsiveness. Model genes harbored recurrent alterations and showed significant correlations with anticancer agents. All six genes were upregulated at mRNA and protein levels in metastatic HCC cell lines versus normal hepatocytes. CONCLUSIONS: We systematically explored the landscape of OSIRDEGs in HCC, and proposed a validated six-gene signature that refines prognostic stratification, delineates immunerelevant HCC subtypes and highlights candidate biomarkers for therapeutic selection and mechanistic investigation.

Humans↗