International Journal of Biological Markers最新文献

Increasing evidence showed that altered histone deacetylases (HDACs) are involved in, and exert cell type specific roles in sarcomagenesis. Here we reviewed expression and roles of HDACs in several types of human sarcomas, providing a basic guideline for personalized therapy. In sarcomas, overexpression of HDACs was common, including a prevalence in uterine sarcomas. Class I HDAC1-3, especially HDAC1-2, were upregulated in most sarcomas and were often associated with poor prognosis. Class I HDACs inhibit tumor suppressor expression and lineage differentiation, but maintain chromatin integrity and oncofusion protein stability. Class II HDACs have specific functions in cellular transformation, long telomeres maintenance, drug resistance, and cytoskeletal organization, and act as negative predictors in some sarcomas; for example, HDAC4 for leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS), HDAC5 for uterine LMS, HDAC6 for ESS, chondrosarcoma (CHS) and undifferentiated endometrial sarcoma. Moreover, some HDACs play dual, cell-context or cellular localization-dependent roles. HDAC2 and HDAC5 could promote or suppress osteosarcoma growth. HDAC4 acts as a tumor suppressor in CHS but as an oncogene in other sarcomas. Moreover, HDAC4 is the targets of several microRNAs in osteosarcoma. Cytoplasmic HDAC6 increases self-renewal and cell migration, compared with nuclear HDAC6 enhancing EWSR1-FLI1 transcription. Thus, the diverse expression and roles of HDACs in sarcoma pathogenesis will be a solid foundation to guide personalized therapeutic application of HDAC modulators in sarcomas.

BackgroundThe Cancer Genome Atlas (TCGA) molecular classification has advanced risk stratification for endometrial carcinoma but has demonstrated comparable survival outcomes between the microsatellite instability (MSI) and copy-number low (CN-L) subtypes. In this study, we aimed to identify potential autophagy-related molecular signatures to increase the precision of TCGA-based prognostic stratification in early-stage endometrial carcinoma.MethodsUnivariate Cox regression analysis of the TCGA-Uterine Corpus Endometrial Carcinoma cohort was used to identify autophagy-related genes associated with survival outcomes in patients with endometrial carcinoma. The candidates were analyzed by the Kaplan-Meier method. Multivariate Cox regression was used to assess whether PEA15 served as an independent prognostic factor, especially for the MSI and CN-L subtypes. We examined the correlation between PEA15 protein expression and patient survival through immunohistochemical analysis of tissue microarrays from our institutional cohort of stage I endometrial cancer patients.ResultsUnivariate analysis revealed that NRG3, PEA15, DNAJB1, BAK1, DRAM1, KLHL24, ATF6, CDKN2A, MBTPS2, and UVRAG were significantly associated with survival outcomes in early-stage endometrial carcinoma patients. Multivariate analysis established PEA15 as an independent prognostic factor. Immunohistochemical analysis of tissue microarrays revealed that elevated PEA15 expression was significantly correlated with poorer overall survival and disease-free survival. Both univariate and multivariate Cox regression confirmed high PEA15 expression as an independent prognostic factor for recurrence in patients with stage I endometrioid adenocarcinoma.ConclusionsThe autophagy-related gene PEA15 is an independent prognostic biomarker in early-stage endometrial carcinoma, improving risk stratification between the MSI and CN-L subtypes. Immunohistochemical detection has clinical potential for molecular classification, offering opportunities for personalized postoperative management strategies.

PurposeAlthough human lysine oxidase-like 3 (LOXL3) is associated with various cancers, its role in pleural mesothelioma (PM) remains uncharacterized. This study investigated the expression level and prognostic association of LOXL3 in PM.MethodsTissue specimens were collected from patients with PM. The expression levels of LOXL3 were assessed using immunohistochemistry, Western blot analysis, and quantitative reverse transcription PCR. The clinical correlation analysis was conducted using R software (version 3.6.3), incorporating data from both The Cancer Genome Atlas and Chuxiong cohorts. Univariate and multivariate Cox proportional hazards regression models alongside Kaplan-Meier survival curve analysis were performed to evaluate prognostic significance. Additionally, gene expression correlation studies between LOXL3 and other members of the LOX family were performed using the Gene Expression Profiling Interactive Analysis platform. Finally, Gene Set Enrichment Analysis was conducted to identify the signaling pathways associated with LOXL3.ResultsLOXL3 exhibited significant upregulation in both sarcomatoid and biphasic PM subtypes compared to the control samples. Clinico-pathological analysis revealed the correlations between LOXL3 expression levels and cancer type, and Wilms tumor protein 1 (WT-1) status. Cox regression analysis identified cancer type as an independent prognostic factor. Kaplan-Meier analysis demonstrated obviously poorer survival rates in cohorts with high LOXL3 expression. Notably, coordinated expression patterns were observed between LOXL3 and LOXL4. The protein expression level of LOXL3 exhibits a positive correlation with CD68, CD206, and programmed death-ligand 1 (PD-L1), with this correlation being particularly pronounced in sarcomatoid mesothelioma. Functional enrichment analysis indicated that high LOXL3 expression was primarily associated with pathways related to oxidative phosphorylation, late and early estrogen response, and adipogenesis.ConclusionLOXL3 is highly expressed in PM and associated with poor prognosis, and is involved in tumor immune evasion. The expression level of LOXL3 is correlated with cancer types and the expression level of WT-1. Cancer type is an independent prognostic factor for PM. LOXL3 expression is positively associated with LOXL4, and high LOXL3 expression is enriched in oxidative phosphorylation, estrogen response, and adipogenesis pathways, while the low-expression group is enriched in apoptosis, interleukin-2/signal transducer and activator of transcription 5, mammalian target of rapamycin complex 1, and transforming growth factor-β pathways. CD68, CD206, PD-L1, and LOXL3 may collaboratively contribute to the regulation of the PM microenvironment and are closely linked to the invasion and metastasis of PM. Therefore, LOXL3 can be used as both a prognostic marker and a potential therapeutic target for PM.

IntroductionMatrix metalloproteinases (MMPs) are enzymes participating in tumorigenesis and tumor progression through their proteolytic and cell-signaling properties. They are regulated mostly by endogenous tissue inhibitors of metalloproteinases (TIMPs). The expression of both MMPs and TIMPs is often altered in cancers. Many studies investigated their potential as circulating cancer biomarkers, with confounding results, which might be induced by preanalytical issues, particularly by using serum instead of plasma. The study aims to investigate plasma levels of selected MMPs and TIMPs in association with the diagnosis and prognosis of colorectal cancer.MethodsThe clinico-pathological data of 148 patients operated for colorectal cancer were collected from the medical records system at the University Hospital Pilsen. Sixty-eight age-matched healthy subjects were included as controls. Plasma levels of MMP-2, -7, -8, -9, -10, and TIMP-1, -2, -3, and -4 were assessed with multiplex immunoassays with the technology xMAP.ResultsMMP-8 and -9 levels were significantly elevated in patients (P= 0.0002 and 0.0009, respectively), TIMP-2 levels were significantly decreased in colorectal cancer patients (P = 0.0016). When comparing the early colorectal cancer (stage I and II) with advanced colorectal cancer (stage III and IV), MMP-8 and TIMP-1 were significantly increased in advanced colorectal cancer (P = 0.0173 and <0.0001, respectively). The area under the curve and the receiver operating characteristic were between 0.680 and 0.530 for all studied biomarkers. In univariate analysis, overall survival was significantly elevated in patients with MMP-7, -8, or TIMP-1, which was higher than cut-offs (hazard ratio = 4.57, 2.03, and 7.64, respectively).ConclusionThese findings suggest that plasma MMP-7, MMP-8, and TIMP-1 are potential prognostic biomarkers for colorectal cancer . None of the investigated biomarkers revealed diagnostic potential.

PurposeThis study aimed to identify genes associated with sensitivity to anti-programmed death-ligand 1 (PD-L1) immunotherapy in lung squamous cell carcinoma (LUSC) using bioinformatics approaches and to validate their functional relevance through in vitro experiments.MethodsTranscriptomic datasets from The Cancer Genome Atlas were analyzed to screen candidate genes, and UBE2C was identified as a key target. Functional enrichment analysis (Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to explore its potential biological roles. To investigate its regulatory effects, UBE2C was overexpressed or silenced in LUSC cells, with or without PD-L1 inhibitor treatment. Real time-quantitative polymerase chain reaction and Western blot were used to assess changes in gene/protein expression and pathway activation. Enzyme-linked immunosorbent assay and lactate dehydrogenase assays were employed to evaluate cytokine secretion (interferon (IFN)-γ, interleukin (IL)-2) and cytotoxicity. Additionally, immunofluorescence was used to examine UBE2C and PD-L1 co-expression in patient tissues stratified by PD-L1 expression levels.ResultsUBE2C expression was significantly higher in PD-L1 high-expression tissues than in low-expression tissues at both messenger RNA and protein levels. Compared with control groups, UBE2C overexpression activated the AKT/PI3 K pathway and increased IFN-γ and IL-2 secretion, whereas knockdown produced the opposite effect. Combined treatment with UBE2C overexpression and a PD-L1 inhibitor further enhanced cytokine release and cytotoxicity relative to PD-L1 inhibitor alone. Immunofluorescence analysis confirmed the co-localization of UBE2C and PD-L1 in tissues with high PD-L1 expression.ConclusionUBE2C was identified as a gene associated with increased sensitivity to anti-PD-L1 immunotherapy in LUSC. Functional experiments suggest that UBE2C may enhance anti-tumor immune responses and improve immunotherapy efficacy, providing a potential biomarker and therapeutic target for personalized treatment.

ObjectiveCervical cancer (CC) is among the most prevalent malignancies globally. Public sequencing data indicate that PAX8-AS1 is associated with gynecological cancers, including CC, but its specific function and mechanism in cervical cancer remain unclear. The present study aimed to elucidate the role of PAX8-AS1 and its target axis in the CC.MethodsA total of 104 CC patients were included. The levels of PAX8-AS1, miR-675-3p, and decorin (DCN) were quantified by quantitative reverse transcription polymerase chain reaction. Survival curve and Cox regression predicted prognostic factors. Proliferation and invasion/migration were assayed by CCK-8 and Transwell in CC cell lines. The target relationship was verified by dual-luciferase reporter assay and co-transfection.ResultsPAX8-AS1 was declined in CC tumor tissue and cell lines. PAX8-AS1 was an independent prognostic factor. PAX8-AS1 expression was associated with the CC pathological including the international federation of gynecology and obstetrics staging system (FIGO), tumor size, and lymph node metastasis. Patients with higher PAX8-AS1 levels had better survival outcomes. Upregulation of PAX8-AS1 inhibited the CC cell invasion, migration, and proliferation. miR-675-3p was predicted and verified as sponged of PAX8-AS1. miR-675-3p was negatively related to PAX8-AS1. PAX8-AS1 impeded the CC cellular function by regulating miR-675-5p. DCN was confirmed as the target of miR-675-5p. DCN was negatively and positively related to miR-675-3p and PAX8-AS1, respectively. PAX8-AS1 suppressed the CC cell invasion, migration, and proliferation by targeting miR-675-3p/DCN axis.ConclusionIn summary, PAX8-AS1 was related to tumor progression and inhibited CC development. As a potential biomarker, PAX8-AS1 impeded CC cell invasion, migration, and proliferation by regulating the axis of miR-675-3p/DCN.

ObjectiveThe objective of this study is to investigate the correlation between the expression levels of midkine (MDK) in the serum of patients with hepatocellular carcinoma (HCC) and various clinical features, and to evaluate the diagnostic efficacy of MDK in HCC cases that are negative for alpha-fetoprotein (AFP).MethodsSerum samples from 330 patients were collected from electronic cases and divided into three groups: HCC, benign liver disease, and healthy people. Serum MDK levels in all three groups were detected by ELISA. Correlation analysis was conducted to evaluate the relationship between serum MDK and liver function indexes and other traditional tumor markers in the HCC group. The receiver operating characteristic curve was used to analyze the diagnostic utility of MDK in HCC and AFP-negative HCC. In addition, univariate and multivariate analyses were performed to determine the correlation between MDK level and tumor metastasis, and clinicopathological features.ResultsMDK is significantly elevated in negative HCC (P = 0.001). The serum expression level of MDK in patients with HCC was found to be positively correlated with various indicators of liver injury (P < 0.05). Notably, elevated MDK expression was significantly associated with the China liver cancer staging system (CNLC) stage (P = 0.003) and complications (P = 0.000). Furthermore, the CNLC stage significantly impacted patient survival and metastasis (P = 0.016). Specifically, we propose that high levels of MDK expression are closely linked to poor tumor prognosis.ConclusionThe risk of tumor metastasis and the likelihood of poor prognosis in patients with HCC are significantly elevated in those exhibiting high levels of MDK. MDK could serve as a novel serum diagnostic marker for patients who are negative for AFP.

Background: Several studies have suggested an association between tumor-associated autoantibodies (TAAbs) and breast cancer. However, most research has focused on imaging techniques, with few studies examining the combined use of TAAbs and imaging to distinguish benign and malignant breast nodules.

Methods: Our study included 197 women with breast nodules. We collected clinical data, preoperative breast ultrasonography, and mammography results. Serum TAAbs were detected using enzyme-linked immunosorbent assay. Logistic regression analysis assessed the ability of factors to distinguish benign from malignant nodules. Receiver operating characteristic curves were plotted, and predictive models were constructed.

Results: Five TAAbs (BRCA2, TP53, ATAD2, NY-ESO-1, CAGE) exhibited significant differences (p < 0.001) between benign and malignant breast nodules, with specificity of 95.83% (area under the curve  = 0.722). Pearson's χ² results revealed a close association between the levels of 5-TAAbs and breast cancer stages. Additionally, preoperative 5-TAAbs combined with ultrasonography and mammography increased diagnostic accuracy of benign nodules by 10.42% and reduced misdiagnosis of malignant nodules by 14.85%. Multivariate logistic analysis identified age (p < 0.001), preoperative 5-TAAbs (p = 0.004), breast ultrasonography (p = 0.01), and mammography (p < 0.001) as independent factors for malignant nodules. Combining 5-TAAbs with age and imaging improved differentiation, achieving sensitivity of 85.42% and specificity of 94.06%.

Conclusion: Tumor-associated autoantibodies, especially the 5-TAAbs, have certain clinical value in the early diagnosis of breast cancer and can serve as an effective auxiliary tool for preoperative breast ultrasonography and mammography in patients with breast nodules.