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Exploring shared biomarkers and their mechanisms in thyroid cancer and systemic lupus erythematosus via bioinformatics analysis.

BACKGROUND: Systemic lupus erythematosus (SLE), an autoimmune disorder, is linked to a heightened risk of multiple malignancies, including thyroid cancer. Thyroid cancer is the most prevalent malignancy of the endocrine system, and its autoimmune-related pathological features render it an optimal subject for investigating the mechanisms of their comorbidity. The molecular mechanisms underlying this comorbidity are still ambiguous. The accurate diagnosis and treatment of thyroid cancer urgently necessitate innovative molecular targets that extend beyond conventional pathological characteristics. This study seeks to employ integrated bioinformatics approaches to elucidate potential shared molecular mechanisms and immunological features between thyroid cancer and systemic lupus erythematosus (SLE), aiming to enhance understanding of their comorbidity and identify novel intervention targets. METHODS: This study initially acquired gene expression data for TC and SLE from the GEO database and subsequently screened and identified differentially expressed genes (DEGs) shared by both diseases. Subsequently, we conducted Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome functional enrichment analyses on these 46 shared differentially expressed genes (DEGs) and further assessed the activation status of pertinent pathways using Gene Set Enrichment Analysis (GSEA). Subsequently, we employed CIBERSORTx to examine immune infiltration patterns and developed protein-protein interaction networks utilising the STRING database. We identified hub genes utilising the MCODE and cytoHubba plugins and visualised the findings with Cytoscape software. We additionally assessed the diagnostic efficacy of these core hub genes in an independent dataset utilising ROC curves and investigated their prognostic relevance in thyroid cancer through Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression. Ultimately, we employed the Network Analyst platform to forecast transcription factor-gene and miRNA-gene regulatory networks and identified potential targeted therapeutic compounds utilising the DSigDB database. RESULTS: This study identified 46 differentially expressed genes (DEGs) commonly linked to thyroid cancer and systemic lupus erythematosus (SLE), which were significantly enriched in signalling pathways associated with immune-inflammatory activation, type I interferon responses, and complement pathway activation. Moreover, GSEA findings validated that immune-inflammatory and autoimmune-related pathways are markedly activated in both conditions. Twelve hub genes were discerned through protein-protein interaction networks. Analysis of immune infiltration indicated that thyroid cancer and systemic lupus erythematosus exhibit a shared characteristic of innate immune dysregulation, marked by the infiltration of myeloid cells (neutrophils, M0/M2 macrophages). Receiver operating characteristic (ROC) curve analysis identified six significant core hub genes with substantial diagnostic value: C1QB, LCN2, C1QC, LTF, VSIG4, and C3AR1. Univariate survival analysis indicated that elevated expression of C1QC and C3AR1 significantly enhances overall survival in thyroid cancer patients; however, multivariate COX regression analysis revealed that their independent prognostic significance necessitates further validation. This study predicted the interaction networks of transcription factors and miRNAs regulating key genes, with LCN2 demonstrating the highest connectivity to miRNAs, and identified candidate therapeutic compounds linked to it. CONCLUSION: This study employed bioinformatics analysis to identify critical shared hub genes and molecular pathways connecting thyroid cancer and systemic lupus erythematosus, offering novel insights into their shared pathogenesis and the advancement of targeted biomarkers and therapeutic strategies.

Bioinformatics analysis

Atrophie blanche lesions closely resembling malignant atrophic papulosis (Degos' disease) in systemic lupus erythematosus.

Two patients with systemic lupus erythematosus are described who in the course of their disease developed small atrophie blanche lesions that closely resembled those found in malignant atrophic papulosis. Preliminary investigation of these two cases indicates that considerable similarities probably exist in the pathogenesis of malignant atrophic papulosis and the atropie blanche lesions of systemic lupus erythematosus. It is concluded that a diagnosis of malignant atrophic papulosis should only be made after systemic lupus erythematosus has been excluded by full investigation.

Adult

Cardiopulmonary manifestations of systemic lupus erythematosus.

Nine of 17 patients (52%) with systemic lupus erythematosus participating in a controlled prospective study were found to have maximal mid-expiratory flow rates suggestive of obstructive or obstructive and restrictive pulmonary disease. Cigarette smokers with systemic lupus erythematosus had significantly lower (P less than .05) maximal mid-expiratory flow rates than either non-smokers with systemic lupus erythematosus or smokers with degenerative joint disease. By echocardiography, pericardial thickening was seen in six of 17 patients (41%) and mitral valvular abnormalities were noted in four of 17 (24%) patients with systemic lupus erythematosus. Echocardiography was found to be an effective means of detecting pericardial disease in patients with systemic lupus erythematosus.

Adolescent

Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus often possess antibodies against two nuclear antigens called Sm and RNP (ribonucleoprotein). We have established the molecular identity of these antigens by analyzing immune precipitates of nuclear extracts from mouse Ehrlich ascites cells labeled with (32)P and (35)S. Anti-Sm serum selectively precipitates six small nuclear RNA molecules (snRNAs); anti-RNP serum reacts with only two of these; and a third serum, characterized as mostly anti-RNP, precipitates a subset of three snRNA bands. Three of the six RNAs are identified by fingerprint analysis as the previously characterized and highly abundant nucleoplasmic snRNA species U1a (171 nucleotides), U1b, and U2 (196 nucleotides). The other three RNAs (U4, U5, and U6) likewise are uridine rich and contain modified nucleotides, but they are smaller, with lengths of about 145, 120, and 95 residues, respectively. Each of the six snRNAs is complexed with and apparently antigenic by virtue of association with specific proteins. All three sera precipitate an identical complement of seven different polypeptides ranging in molecular weight from 12,000 to 35,000; these proteins are abundant in nuclear extracts, but are neither histones nor the major polypeptides comprising the 30S heterogeneous nuclear RNP particles of mammalian nuclei. Our data argue that each of the six snRNAs exists in a separate small nuclear ribonucleoprotein (snRNP) complex with a total molecular weight of about 175,000. We find that human antisera also precipitate snRNAs from a wide range of vertebrate species and from arthropods. We discuss the antigenic snRNPs in relation to the published literature on snRNAs and nuclear RNPs and consider possible functions of snRNPs in nuclear processes.

Antibodies, Antinuclear

Laboratory criteria for a diagnosis of systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) and other connective tissue diseases were surveyed for the presence of antibodies to normal DNA, antibodies to a ribonuclease-insensitive acidic nuclear protein, and immune deposits in normal skin. While 80% of patients with SLE had abnormal values for at least two of these three tests, none of the patients with other connective tissue diseases had more than one abnormal value. The presence of RBC autoantibodies was found along with one of the other abnormal laboratory tests in 76% of patients with SLE, including 14% of patients not found to have two abnormal tests. None of the other patients tested had RBC autoantibodies. These findings suggest that a set of laboratory tests can be constructed as criteria for a diagnosis of SLE that would be as specific as the presently employed American Rheumatism Association criteria.

Antibodies, Antinuclear

Recurrent venous thrombosis with a "lupus" coagulation inhibitor in the absence of systemic lupus.

A young man presenting with recurrent deep venous thrombosis was found to have a lupus type coagulation inhibitor. He showed neither clinical nor serological evidence of systemic lupus. The value of the Russell viper venom coagulation time in the detection of the inhibitor is demonstrated. Anticoagulant therapy has not caused any bleeding complication despite the presence of the inhibitor.

Adult

[Headache in the pathology of small cerebral blood vessels: study of patients with systemic lupus erythematosus].

Seventy-two records of patients with systemic lupus erythematosus were reviewed retrospectively. Sixty-one fulfilled the criteria for the disease. Forty-six percent had clinical evidence of central nervous system involvement. The incidence of headache was compared in those with and without central nervous system lupus. No difference in the frequency of headache in the two groups was found and the incidence of hypertension, renal disease and steroid therapy was equally distributed among those with and without headache. A significantly higher incidence of hypertension was found in patients with central nervous system lupus erythematosus. We conclude that headache in systemic lupus erythematosus in the absence of neurologic symptoms or signs is no indication of central nervous system involvement by the process and that small vessel disease of the brain is not a cause of headache.

Adolescent

Hydralazine therapy in hypertensive patients with idiopathic systemic lupus erythematosus.

Seven hypertensive patients with idiopathic systemic lupus erythematosus were treated with hydralazine. They received a mean daily dose of 203 mg for a mean duration of 21 months. All were taking prednisone alone or in combination with azathioprine. During therapy with hydralazine, there were no new symptoms nor exacerbation of pre-existing symptoms attributable to systemic lupus. Laboratory parameters, including antinuclear antibody titers and complement levels, either improved or remained stable. The results indicate that hydralazine can be safely used in hypertensive patients with systemic lupus who are receiving concomitant immunosuppressive therapy.

Adult

NIH conference. Systemic lupus erythematosus: evolving concepts.

Systemic lupus erythematosus, a disease of unknown cause and protean manifestations, continues to excite substantial investigational interest. These papers bring together recent advances in concepts of its immunopathogenesis, evidence for a major genetic role in the causation of the process, developing systems for the morphologic assessment of its often fatal nephritis, and data from ongoing trials of cytotoxic drugs in its management.

Adolescent

Complement system studies in systemic lupus erythematosus (SLE)

Complement system involvement has been studied in 16 patients with systemic lupus erythematosus (SLE). Circulating conversion products of C3 were observed in 4 cases. Low mean values of C4 and C3 were found, while C3 proactivator (properdin factor B) levels were low in only a few of the patients. The levels of C4, C3 and C3 proactivator were not lower in the 4 patients in whom C3 conversion products could be demonstrated than in the others. It is concluded that the low complement values found in SLE may be caused mainly by deficient synthesis. Signs of complement activation are in this patient material demonstrated early in the disease, and chiefly in patients not receiving immunosuppressive therapy.

Adolescent

Oral contraceptive therapy and systemic lupus erythematosus.

The relationship between oral contraceptive therapy and systemic lupus erythematosus is not well defined. It has been reported that oral contraceptives may induce lupus: they may also exacerbate pre-existing disease. This report concerns a young woman in whom systemic lupus erythematosus developed three weeks after the commencement of oral contraceptive therapy, but who was shown to have had a chronic biological false positive serological test for syphilis for eight months prior to this. The significance of false positive serological tests for syphilis and the effect of female sex hormones on disease activity in systemic lupus erythematosus is discussed.

Adult

Acute adverse reactions to ibuprofen in systemic lupus erythematosus.

Three young women with systemic lupus erythematosus who were given ibuprofen for arthritis voluntarily discontinued taking the drug. On reinstitution of therapy, profound hypotension, fever, and headaches developed within hours, without other identifiable cause. A possible relationship to salicylate intolerance was considered. Because of these apparent side effects, we stress caution in the use of ibuprofen in systemic lupus erythematosus, particularly if there is any history of salicylate intolerance.

Acute Disease

Serum factors releasing serotonin from normal platelets: relation to the manifestations of systemic lupus erythematosus.

In 13 patients with systemic lupus erythematosus, globulin fractions of sera from serial bleedings were assayed for the induction of serotonin release from normal platelets. Releasing activity appeared at some time in the sera of seven patients, five of whom had episodes of thrombocytopenia. Conversely, only one patient manifested thrombocytopenia without the occurrence of serotonin releasing activity at any time. In three patients with episodes of thrombocytopenia, increases in serotonin releasing activity temporally coincided with drops in platelet count. These data show that levels of circulating platelet serotonin releasing factor(s) vary in the course of systemic lupus erythematosus and these variations may be inversely related to the platelet count in particular patients.

Adult

Influenzal vaccine response in systemic lupus erythematosus.

The response of patients with systemic lupus erythematosus and normal subjects to systemic immunization and boosting with influenza A vaccines was studied. Symptoms after vaccination were somewhat more frequent in the patients than in the normal subjects; however, all symptoms were minor and no major flare of illness occurred. No significant induction or increase of pre-existing autoantibodies among the patients was detected after vaccination. The immunogenecity of the vaccinations, as assessed by antibody titers, was similar in the patient and control groups. No correlation between serologic response to influenzal antigens and HLA was found. Thus, in this group of patients with systemic lupus erythematosus, who were either in remission or had mild-to-moderate disease activity, killed influenzal vaccination caused no apparent worsening of disease activity.

Adult

[Neuropsychic manifestations in systemic lupus erythematosus (author's transl)].

Thirty-three cases of systemic lupus erythematosus in women are studied in retrospect. Eight patients (24 percent) presented a total of ten neuropsychiatric episodes that could be attributed to the underlying disease. The neuropsychiatric manifestation that was most often observed was cerebrovascular stroke (40 percent) followed by psychic disturbances and convulsions. A facial paralysis coinciding with an hypertensive crisis was noticed in one case. Another patient presented a peripheral sensitive neuropathy. Five episodes occurred prior to diagnosis or during the first year of the disease. In two patients the neuropsychiatric manifestations constituted the initial symptom of systemic lupus erythematosus. ECG proved to be one of the most valuable diagnostic tools among the complementary studies. It was altered in cases of organic pathology and normal when disturbances were of psychic origin. The C3 fraction of the serum complement revealed a definite difference between patients with and without neuropsychiatric manifestations. Concentrations were lower in persons which psychic disturbances than in patients without them. The pathogenesis of neuropsychiatric manifestations of systemic lupus erythematosus is discussed. They cannot be attributed exclusively to coagulation disturbances nor to treatment with corticosteroids. The immediate prognosis of neuropsychiatric episodes was good: there was partial or total recuperation in eight of the ten episodes. However, the long-term course of systemic lupus erythematosus shows that these manifestations represent an unfavourable prognostic factor in this disease.

Adolescent

Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus. Association of high avidity antinative DNA antibody with glomerulonephritis.

Significant differences in both specificity and avidity of anti-DNA antibodies were observed in the sera of groups of patients with active systemic lupus erythematosus glomerulonephritis, active systemic lupus erythematosus without nephritis, and in IgG eluates obtained by DNAase digestion of isolated glomeruli from glomerulonephritic kidneys. With methylated albumin-kieselguhr fractionated 3H-HeLa DNA as a source of native or single-strand DNA antigen in a modified Farr assay, an increased level of antibody to native DNA was associated with active systemic lupus erythematosus, particularly active nephritis. The avidity of antinative DNA estimated from plots of the reciprocals of bound and free antigen according to the Sips distribution formula was significanly lower in active glomerulonephritis sera than in sera from patients with active systemic lupus erythematosus without nephritis. However, antinative DNA of uniformly high avidity was found in the glomerular eluates. Avidity of single-strand DNA antibodies did not differ in the various patient groups. The data stronly supprot a major role for high avidity antinative-DNA in DNA/antiDNA immune complex-induced glomerular injury in systemic lupus erythematosus.

Antibodies, Anti-Idiotypic

Migrainous phenomena in systemic lupus erythematosus.

Eleven patients with systemic lupus erythematosus (SLE) also had headaches and/or visual hallucinations typical of those found in migraine. These migrainous symptoms were commonly associated with exacerbations of SLE and abated as disease activity subsided. In some cases corticosteroids were more effective than conventional antimigraine therapy in controlling headaches and scotomas. The data suggest that migraine-like phenomena may arise as a result of vascular dysfunction in SLE.

Adult

Deposition of antibodies to a soluble cytoplasmic antigen in the kidneys of patients with systemic lupus erythematosus.

Two patients with systemic lupus erythematosus were studied whose sera contained precipitating antibodies to a soluble cytoplasmic antigen, termed Ro. A reduction in the amount of these antibodies in each case was accompanied by a deterioration in the clinical status with the development of nephritis leading to death. Acid elution of gamma globulin was performed from homogenates of the renal cortex, and in both instances antibodies to Ro were demonstrated in the eluates by double immunodiffusion. The titer of these antibodies was measured in both sera and eluates, and specific enrichment of anti-Ro in the eluates was demonstrated in both patients. This strongly suggests the direct participation of Ro-anti-Ro immune complexes in the progressive renal disease and may underlie the association seen here between the decreasing serum titers of antibodies to Ro and the clinical deterioration in these two cases.

Antibody Specificity