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PubMed2024

Biomarkers related to m6A and succinic acid metabolism in papillary thyroid carcinoma.

BACKGROUND: Studies have shown that m6A modification is related to the occurrence and development of papillary thyroid carcinoma (PTC). The disorder of succinic acid metabolism is associated with the occurrence and development of various tumors. However, there are few studies based on m6A and succinate metabolism-related genes (SMRGs) in PTC. METHODS: The TCGA-Thyroid carcinoma (THCA), GSE33630, 1159 SMRGs, and 23 m6A regulatory factors were collected from the online databases. Subsequently, the differentially expressed genes (DEGs) were selected between PTC (Tumor) and Normal samples. The overlapping genes among the DEGs, m6A, and SMRGs were applied to screen the biomarkers. Using the 3 machine-learning algorithms, the biomarkers were determined based on the overlapping genes. Next, the biomarkers were evaluated by the ROC curve and expression analysis in TCGA-THCA and GSE33630. Then, the overall survival (OS) differences were compared between the high-and low-expression biomarkers. Finally, immune infiltration analysis, molecular regulatory network, and drug prediction were performed based on the biomarkers. RESULTS: In TCGA-THCA, there were 2800 DEGs between and Normal samples, and then 7 overlapping genes were obtained. Importantly, ADK, TNFRSF10B, CYP7B1, FGFR2, and CPQ were determined as biomarkers with excellent diagnostic efficiency (AUC > 0.7). In PTC samples, ADK and TNFRSF10B were high-expressed while CYP7B1, FGFR2, and CPQ were low-expressed. Especially, the high-expression groups of ADK had a better prognosis, while the high-expression groups of CYP7B1, FGFR2, and CPQ had a worse prognosis. Afterward, immune infiltration analysis found that 16 immune cells had infiltration differences between the Tumor and Normal samples. Finally, transcription factor SP1 could regulate CYP7B1 and TNFRSF10B. Moreover, Navitoclax was a potential drug for PTC patients. CONCLUSION: Overall, we described 5 biomarkers associated with adverse prognosis of PTC, including ADK, TNFRSF10B, CYP7B1, FGFR2, and CPQ. All these biomarkers were involved in succinate metabolism and m6A modification of RNA. This set of biomarkers should be explored further for their diagnostic value in PTC. Investigations into the mechanistic role of alteration of succinate metabolism and m6A modification of RNA pathways in the pathophysiology of PTC are warranted.

Humans↗
PubMedDate not supplied

The biology of colorectal carcinoma.

Rapid progress in understanding the biology of colorectal carcinoma has occurred in the last decade. During this time, the importance of tumor suppressor genes has been delineated. Mutations in proto-oncogenes, and some of the genetic and epigenetic defects that occur during neoplastic transformation, have been characterized. The very recent identification of a technology that detects some mutations in genes by analyzing fecal specimens offers the real prospect of effective, low-cost screening of large segments of the population at risk for the development of large bowel cancer. A better understanding of the mechanisms involved in metastasis is slowly leading to better methods of prognostication for patients with carcinoma of the colon or rectum. This is important because a better biologic identification of patients at high risk for subsequent metastasis will help determine which patients should receive adjuvant therapy. Further, the development of new approaches to inhibit various aspects of the cascade of events necessary to produce metastasis, notably the inhibition of neovascularization, suggests the real possibility that established metastases may be treated by relatively nontoxic medical therapies. As a result, further knowledge of the biology of colorectal cancer will translate into strategies that will continue to improve the control of this prevalent carcinoma.

Adenoma↗
PubMed1992

Simian virus 40 large tumor antigen alone or two cooperating oncogenes convert REF52 cells to a state permissive for gene amplification.

Gene amplification is characteristic of tumors and continuous cell lines but not of primary, normal, diploid, senescing cells. However, the rat cell line REF52, which resembles primary cells in requiring expression of cooperating oncogenes for transformation, is unusual among cell lines as it is not permissive for amplification. REF52 cells did not form colonies in N-(phosphonacetyl)-L-aspartate (PALA), a drug for which the only known mechanism of resistance is amplification of the carbamoylphosphate synthetase/aspartate transcarbamoylase/dihydroorotase (CAD) gene. Colonies did form in a low concentration of methotrexate but did not contain amplified dihydrofolate reductase genes. Expression of two cooperating oncogenes in REF52 cells converted them to a state permissive for amplification. Cells expressing only the 12S E1A mRNA of adenovirus 5 did not give rise to PALA-resistant colonies, but expression of an activated ras gene together with E1A readily allowed the cells to form resistant colonies in which the CAD gene was amplified. Cells expressing E1A plus ras were fully transformed, but expression of simian virus 40 large tumor antigen alone converted REF52 cells to a state permissive for amplification without transforming them fully. The ability to manipulate gene amplification in REF52 cells by expression of oncogenes should contribute to an understanding of the nature of the permissive state.

Adenovirus Early Proteins↗
PubMed1992

Philadelphia chromosome-positive leukaemia: the translocated genes and their gene products.

Overwhelming evidence indicates a role for the deregulated ABL protein tyrosine kinase in the aetiology of CML and Ph-positive acute leukaemia. These disorders are characterized by the generation of BCR/ABL fusion proteins with elevated tyrosine kinase activity. Although much is known concerning the transforming potential of ABL proteins in various systems, very little is understood of the normal function and mode of regulation of ABL activity. The mechanism of oncogenic activation is therefore also obscure. In spite of this, our understanding of the molecular details of these chromosomal translocations allows the design of therapies directed against their unique, leukaemia-specific proteins and RNA products.

Abelson murine leukemia virus↗
PubMed1992

Hepadnavirus integration: mechanisms of activation of the N-myc2 retrotransposon in woodchuck liver tumors.

In persistent hepadnavirus infections, a distinctive feature of woodchuck hepatitis virus (WHV) is the coupling of frequent viral integrations into myc family genes with the rapid onset of primary liver tumors. We have investigated the patterns of WHV DNA insertion into N-myc2, a newly identified retroposed oncogene, in woodchuck hepatomas resulting from either natural or experimental infections. In both cases, integrated viral sequences were preferentially associated with the N-myc2 locus. In more than 40% of the woodchuck tumors analyzed, viral insertion sites were clustered in a 3-kb region upstream of N-myc2 or in the 3' noncoding region. Insertion of WHV sequences homologous to the human hepatitis B virus enhancers, either upstream or downstream of the N-myc2 coding domain, was associated with the production of normal N-myc2 mRNA or hybrid N-myc2-WHV transcripts, initiated at the normal N-myc2 transcriptional start site. Transient-transfection assays with different N-myc2-WHV constructs in HepG2 cells demonstrated that the viral enhancers could efficiently activate the N-myc2 promoter. These results, showing that cis activation of preferred cellular targets through enhancer insertion is a common strategy for tumor induction by WHV, emphasize the previously noted similarities between hepadnaviruses and nonacute oncogenic retroviruses.

Animals↗
PubMed1992

The retinoblastoma gene product suppresses neu oncogene-induced transformation via transcriptional repression of neu.

The retinoblastoma susceptibility gene (Rb) is a tumor suppressor gene involved in the etiology of many types of human cancers. However, the molecular mechanisms involved in tumor suppression by Rb are largely unknown. The neu gene is a dominant transforming oncogene and a member of the growth factor receptor tyrosine kinase gene family. Both inactivation of the Rb gene and overexpression of the neu gene are involved in human breast and lung cancers. Therefore, it is of interest and importance to investigate the potential interactions between Rb and neu. Here we show that Rb suppresses neu-induced transformation by focus formation assays. This transformation suppression by Rb was further shown to be due to transcriptional repression of neu using Rb expressing effector plasmid and neu promoter-chloramphenicol acetyltransferase reporter gene. The cis-acting element conferring Rb-mediated repression was mapped to a recently identified novel enhancer in the neu promoter. The data indicate that the growth factor receptor neu is a target for the Rb gene product and transcriptional repression of a dominant oncogene expression may be one of the molecular mechanisms of Rb-mediated tumor suppression.

3T3 Cells↗
PubMed1992

Genomic rearrangements in mouse C3H/10T1/2 cells transformed by X-rays, UV-C, and 3-methylcholanthrene, detected by a DNA fingerprint assay.

Genomic rearrangements occurring in C3H/10T1/2 cells transformed by X-rays were examined with a DNA fingerprint assay. Four multilocus and multiallele probes were employed (M, X, H10, and H16) that detect different families of minisatellite sequences dispersed throughout the genome. Genomic rearrangements were detectable only with probe M. This specificity may be explained by a genomic instability owing to a specific sequence or structure of DNA recognized by probe M. Genomic rearrangements were detected in 5 of 12 type III foci transformed by 600 cGy of X-rays and in all clones isolated from a previously transformed clone exposed to a second dose of 600 cGy and recloned. The latter data suggest that the stage of transformation and the occurrence of genomic rearrangement induced by X-rays may be related. An intensity shift or a complete deletion of band 2 was common to these X-ray-induced clones, as well as to clones transformed by UV-C (1 of 5) or 3-methylcholanthrene (4 of 6). This band did not hybridize to probes for the retinoblastoma gene RB or for p53. We hypothesize that the loss of band 2 may reflect a significant genetic change in the transformation of 10T1/2 cells, perhaps representing the inactivation of a tumor suppressor gene other than RB or p53. Additional rearrangements occurred in X-ray-transformed clones; these rearrangements were not observed with the other carcinogens. Aside from the changes in band 2, however, no specific pattern of genomic rearrangement was associated with X-ray transformation, and the presence or absence of rearrangements did not correlate with tumorigenicity in syngeneic nonimmunosuppressed C3H mice.

Animals↗
PubMed2003

scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila.

Cancer is a multistep process involving cooperation between oncogenic or tumor suppressor mutations and interactions between the tumor and surrounding normal tissue. Here we present the first description of cooperative tumorigenesis in Drosophila, by using a system that mimics the development of tumors in mammals. We have used the MARCM system to generate mutant clones of the apical-basal cell polarity tumor suppressor gene, scribble, in the context of normal tissue. We show that scribble mutant clones in the eye disc exhibit ectopic expression of cyclin E and ectopic cell cycles, but do not overgrow due to increased cell death mediated by the JNK pathway and the surrounding wild-type tissue. In contrast, when oncogenic Ras or Notch is expressed within the scribble mutant clones, cell death is prevented and neoplastic tumors develop. This demonstrates, for the first time in Drosophila, that activated alleles of Ras and Notch can act as cooperating oncogenes in the development of epithelial tumors, and highlights the importance of epithelial polarity regulators in restraining oncogenes and preventing tumor formation.

Animals↗
PubMed1992

Epstein-Barr virus and Burkitt's lymphoma.

Recent investigations indicate that Burkitt's lymphoma consists of several subtypes, defined by their clinical and molecular features. Each geographical region so far studied appears to consist of a different mixture of subtypes. Interestingly, there appear to be geographic 'gradients' with respect to the fraction of tumors associated with EBV and the type of 8;14 chromosomal translocation. The rate of EBV association is highest in Equatorial Africa, lowest in North America and intermediate in South America. The fraction of tumors with breakpoints far upstream of the c-myc gene follows a similar pattern. These findings strongly suggest that the subtypes of Burkitt's lymphoma are environmentally determined, and we propose that the pattern of infection (e.g. malaria) to which the young child is exposed influences the tumor subtype distribution by altering the relative and absolute numbers of various B cell precursors at sites of B cell ontogeny (the bone marrow, and possibly mesentery). These B cell precursors are the cells which are susceptible to the specific chromosomal translocations associated with Burkitt's lymphoma. We further propose that immunoglobulin enhancers (recognized and unrecognized) both influence the likelihood of the translocation occurring, and in at least a fraction of cases, contribute to the deregulation of a c-myc. EBV, via EBNA-1, the only invariably expressed latent-gene in Burkitt's lymphoma, probably influences c-myc expression in Burkitt's lymphoma by increasing immunoglobulin enhancer function. Thus, in effect, EBV collaborates with the translocations associated with Burkitt's lymphoma in causing c-myc deregulation. This collaboration is independent of the breakpoint location. While other molecular abnormalities must be able to contribute to myc deregulation in the same way, EBV association in Burkitt's lymphoma is probably determined by the age at which EBV infection occurs (being more likely when infection occurs in very young children) and perhaps also by other infectious diseases that numerically influence the fraction, and predominant stage of differentiation (and hence translocation breakpoint sites) of immature B cells infected by EBV. The presence of EBV in many such cells greatly increases the incidence rate of Burkitt's lymphoma, since one of the genetic lesions needed to deregulate c-myc is already present.

Burkitt Lymphoma↗
PubMed1992

Chromosome losses in tumorigenic revertants of EJ/ras-expressing somatic cell hybrids.

Tumorigenic transformation of SV40-immortalized human uroepithelial cells (SV-HUC) after transfection with EJ/ras was previously reported to be a rare event. To test the hypothesis that ras transformation requires loss of suppressor genes, somatic cell hybrids were generated between a rare tumorigenic transformant and an isogeneic nontumorigenic EJ/ras transfectant obtained in the same experiment. Both parental cell lines, as well as all hybrid progeny, expressed mutant p21 ras protein, but injections of three such independent hybrids into athymic nude mice at passage (P) 4 demonstrated that tumorigenicity was suppressed at 20 of 22 sites. Two tumors developed, after a relatively long 17-week latent period, as compared with a 4-week latent period for the tumorigenic parent. All three hybrids produced tumors at P8, but these showed different latent periods (3-14 weeks). Revertant hybrid tumors were high-grade carcinomas. Cell lines derived from these tumors expressed mutant p21 ras and retained at least 1 EJ/ras integration site. Karyotypic analysis of six independent hybrid tumor revertants showed that each had a unique clonal karyotype. Losses of two or more homologues of 1p, 3p, 4, 8, 10p, 11p, 13q, and 18 were identified in one or more tumorigenic revertants. Losses of all these chromosomes were previously associated with transformation of SV-HUC by EJ/ras, but were also associated with chemical transformation of SV-HUC in tumors that did not express mutant ras. Genetic losses involving most of these chromosomes have also been identified in clinical bladder cancers (i.e., 1p, 3p, 8, 11p, 13 and 18q). These data show that expression of EJ/ras does not negate or significantly alter requirements for multiple genetic losses in HUC tumorigenesis.

Animals↗
PubMed1992

Altered structure and expression of the p53 gene in human neuroepithelial tumors.

The p53 gene, located on chromosome 17p13.1, may be important in the pathogenesis of human neuroepithelial tumors, because it is a tumor suppressor gene and genetic alteration is essential for certain human cells to acquire the neoplastic phenotype. The structure and expression of the p53 gene were investigated in cultured human glioma cells and biopsied specimens of neuroepithelial tumors. Immunocytochemical examination of p53 gene expression revealed positive nuclear staining in six of seven glioma cell lines tested. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis demonstrated unequivocal heterogeneity of migration rate in p53 bands. Pulse-chase analysis clearly showed an increased half-life of p53 in cultured human glioma cells. These abnormalities are presumably due to genetic alterations in the p53 gene. Nucleotide substitutions in exon 5, 7, or 8 of the p53 gene could be detected by polymerase chain reaction-single strand conformational polymorphic analysis in four of seven (57%) human glioma cell lines, and nine of 29 (31%) biopsied specimens of neuroepithelial tumors examined. The present results indicate that genetic alterations in the p53 gene are responsible for the tumorigenesis of at least some human neuroepithelial tumors.

Astrocytoma↗
PubMed1992

Prognostic factors in node-negative breast cancer.

One hundred patients with node-negative breast cancer were examined to analyze the influence of tumor size, nuclear grade, and DNA content determined by flow cytometry on overall survival. Patients with diploid cancers lived significantly longer than those with aneuploid cancers (126 +/- 8 vs 80 +/- 11 months). Patients with an S-phase fraction less than 10% lived significantly longer than those with S-phase fractions 10% or greater (122 +/- 8 vs 85 +/- 10 months). Tumor size had the major impact on survival, and multivariate analysis of variance by the Cox proportional hazards model showed the greatest effect on prognosis. Tumor grade did not significantly influence overall survival.

Breast Neoplasms↗
PubMed1992

Primitive neuroectodermal tumors after prophylactic central nervous system irradiation in children. Association with an activated K-ras gene.

Three patients had supratentorial malignant brain tumors 7 to 9 years after prophylactic central nervous system (CNS) treatment for acute lymphocytic leukemia or malignant T-cell lymphoma. Therapy was administered at the age of 3 to 8 years and included cranial irradiation (total dose, 1800 to 2400 cGy) and intrathecal methotrexate. The brain tumors had histologic and immunohistochemical features of primitive neuroectodermal tumors (PNET), including neuroblastic rosettes, rhythmic arrangement of tumor cells, and immunohistochemical expression of glial, and in one patient neuronal, marker proteins. Using polymerase chain reaction-mediated DNA amplification from paraffin-embedded tissues and subsequent DNA sequence analysis, an activating point mutation was detected in the K-ras protooncogene in one tumor. This mutation was a G to A transition in position 2 of codon 12, substituting aspartate (GAT) for glycine (GGT). This type of mutation has not been observed before in human brain tumors, but it is frequent in radiation-induced murine lymphomas. These observations suggest that PNET can be induced after completion of the embryonal and fetal development of the human CNS. Oncogene-activating point mutations may represent a pathogenetic mechanism involved in the genesis of radiation-induced brain tumors.

Aspartic Acid↗
PubMed1992

Incidence of ras oncogene activation in lung carcinomas in Hong Kong.

BACKGROUND: In Hong Kong, lung carcinomas contribute to the majority of cancer deaths among Chinese. Point mutational activation of ras oncogenes has been observed in several populations. The incidence of these mutations in Hong Kong lung carcinomas was investigated. METHODS: Lung resections obtained from 52 Chinese patients whose conditions were newly diagnosed as non-small cell lung cancer, paraffin sections from 29 Chinese patients with previously diagnosed adenocarcinoma of the lung, and paraffin sections from 49 squamous cell carcinomas were examined for the presence of point mutations in Ki-ras codon 12, N-ras codon 61, and Ha-ras codon 12 oncogenes by allele-specific hybridization after specific amplification of appropriate regions of the DNA using the polymerase chain reaction. RESULTS: Among the 130 lung carcinomas investigated, Ki-ras point mutations were detected in seven cases, of which six were adenocarcinomas and one a squamous cell carcinoma. No mutations were detected in the N-ras and Ha-ras codons. CONCLUSIONS: The incidence of Ki-ras codon 12 point mutational activation in Chinese patients with adenocarcinomas was 6 of 63 (9.5%). The incidence of Ki-ras 12 point mutational activation among men with lung adenocarcinomas in Hong Kong (6 of 32 patients, 18.8%) is significantly different from that in women in Hong Kong (0 of 31 patients, 0%). Although ras oncogenes are implicated as having a role in the development of lung adenocarcinomas, especially among smokers, it is clear from these data that they are not associated with the unusually high incidence of lung adenocarcinomas among women in Hong Kong.

Adenocarcinoma↗
PubMed1992

Differentiation and proliferation in mouse embryonal carcinoma cells.

How cell commitment and differentiation are controlled in the early stages of embryogenesis is a problem that has long fascinated developmental biologists. Retinoic acid-induced differentiation of embryonal carcinoma cells in culture provides a model in which these questions can be explored. Recent work has yielded exciting insights into the central series of molecular changes which drives the commitment of these cells to formation of a new phenotype. Interacting with the key molecules in this central pathway is a variety of transcription factors, many of which show changes in availability and/or activity during differentiation. In various combinations, these modulate the activities of genes involved in both cell proliferation and in the production of extracellular matrix and other proteins characteristics of differentiated cells.

Animals↗
PubMed2026

Effect of Tertiary Lymphoid Structures on Immune Cell Infiltration in the Tumor Microenvironment and Prognosis in Lung Adenocarcinoma.

Tertiary lymphoid structures (TLSs) modulate immune responses in various solid tumors, but their comprehensive role in lung adenocarcinoma (LUAD) remains unclear. In this study, we analyzed RNA-seq data from 539 LUAD patients in The Cancer Genome Atlas (TCGA) and microarray data from 223 samples from the Gene Expression Omnibus (GEO, GSE13213, and GSE37745). TLS signatures were evaluated via unsupervised consensus clustering based on 12 chemokine transcriptome signatures. The relationships between TLS and clinical characteristics, tumor microenvironment (TME) cell infiltration, and prognosis were assessed using ESTIMATE and CIBERSORT. A prognostic model was established using LASSO regression and validated with external datasets. Additionally, H&E and IHC analyses were performed to explore associations between intratumoral TLS density, immune-related molecular expression, and patient prognosis in LUAD. Consensus clustering of the TCGA cohort revealed two distinct LUAD patient clusters according to TLS abundance. Cluster 1 exhibited greater immune cell infiltration, more favorable prognosis, and increased expression of immune checkpoint molecules. We developed a prognostic model comprising eight survival-associated genes that act as independent prognostic factors for patient survival. H&E/IHC analyses revealed that TLS density-regardless of pathological stage-was associated with better prognosis; higher intratumoral TLS density/proportion was also related to more favorable outcomes. IHC confirmed that survival-associated genes (CD5, HLA-DMB, and P2RY13) are independent prognostic indicators in LUAD. Our study demonstrated the close relationship between TLS signatures and an active immune microenvironment, highlighting their potential as independent prognostic indicators in LUAD.

Humans↗