Predictive value of m5C regulatory gene expression in pancreatic adenocarcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Yu X
PROVIDER: S-EPMC8410865 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Chemoradioimmunotherapy of patients with pancreatic adenocarcinoma from the CapRI trial did not show any benefit of interferon-? in addition to a 5-fluorouracil (5FU)-based treatment. The aim of this study was to identify immunological parameters in patients from this trial to be used for predictive and/or prognostic purposes.The following methods were used: tumour immunohistology, FACS analyses, cytokine measurement, as well as cytotoxicity and ELIspot. Immunological parameters were correlated with patients' survival using the Kaplan-Meier method.Irrespective of therapy type, high lymphocyte accumulation in tumours and frequencies of NK cells and effector (eff) CD8(+) T cells in peripheral blood of the patients were associated with patients' survival. Amount of CD3(+) and effector-memory CD8(+) blood lymphocytes, expression of CD152 and interleukin (IL)-2 serum level showed a predictive value for chemoradioimmunotherapy. Tumoural accumulation of CD3(+) and CD8(+) cells was predictive for outcome of chemotherapy alone. Besides, we identified the frequencies of CD3(+) lymphocytes, effCD8(+) T cells and NK cells in the peripheral blood of the patients, and IL-10 amount in serum, to be predictive values for 5FU-based chemotherapy.Immunological parameters, identified in this trial as possible markers, may be of interest in personalized medicine towards the improvement of the treatment and prognosis of pancreatic carcinoma patients.
| S-EPMC4366903 | biostudies-other
Project description:Background: A high mortality rate makes hepatocellular carcinoma (HCC) one of the most common types of cancer globally. 5-methylcytosine (m5C) is an epigenetic modification that contributes to the prognosis of several cancers, but its relevance to HCC remains unknown. We sought to determine if the m5C-related regulators had any diagnostic or prognostic value in HCC. Methods: M5C regulatory genes were screened and compared between HCC and normal tissue from The Cancer Genome Atlas (TCGA)and Gene Expression Omnibus (GEO) databases. Least absolute shrinkage and selection operator method (LASSO) and univariate Cox regression analysis of differentially expressed genes were then performed to identify diagnostic markers. A LASSO prognostic model was constructed using M5C regulatory genes with prognostic values screened by TCGA expression data. HCC patients were stratified based on risk score, then clinical characteristics analysis and immune correlation analysis were performed for each subgroup, and the molecular functions of different subgroups were analyzed using both Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). The prognostic model was evaluated using univariate and multivariate Cox analyses as well as a nomogram. Molecular typing was performed according to m5C regulatory genes and immune checkpoint genes expression respectively, and clinical characterization and immune correlation analysis were performed for each subgroup. Results: M5C regulatory genes are expressed differently in HCC patients with different clinical and pathological characteristics, and mutations in these genes are frequent. Based on five m5C regulators (NOP2, NSUN2, TET1, YBX1, and DNMT3B), we constructed a prognostic model with high predictive ability. The risk score was found to be an independent prognostic indicator. Additionally, risk scores can also be applied in subgroups with different clinical characteristics as prognostic indicators. Conclusion: The study combined data from TCGA and GEO for the first time to reveal the genetic and prognostic significance of m5C-related regulators in HCC, which provides new directions for identifying predictive biomarkers and developing molecularly targeted therapies for HCC.
| S-EPMC9465290 | biostudies-literature
Project description:BACKGROUND Pancreatic adenocarcinoma (PAAD) is one of the deadliest types of cancer. In the early stages, patients often have atypical symptoms, making diagnosis difficult. The prognosis of diagnosed patients is very poor and treating PAAD is challenging. Therefore, determining reliable risk factors related to PAAD development is critical for improving patient prognosis. E2F family transcription factors (TFs) are essential regulators of DNA synthesis and cell cycle progression in eukaryotic cells, and they have been identified as prognostic biomarkers associated with multiple cancer types. However, further research is necessary to establish the prognostic relevance of these TFs in PAAD patients. MATERIAL AND METHODS We assessed PAAD patient transcriptional and outcome data using the TIMER, ONCOMINE, STRING, GEPIA, cBioPortal, Kaplan-Meier Plotter, GSCALite, and starBase databases. RESULTS PAAD tumor tissues exhibited increased expression of E2F1/3/5/7/8 relative to that in normal tissues, while the expression of E2F2/3/6/8 was associated with a more advanced tumor stage. Survival analyses indicated that PAAD patients expressing higher levels of E2F1/2/3/7/8 exhibited shorter overall survival (OS) and disease-free survival (DFS) than patients expressing lower levels of these TFs. In addition, E2F4 and E2F6 overexpression was associated with poorer DFS and OS, respectively. We also found that the expression of E2Fs was significantly correlated with immune infiltrates, including CD8+ T cells, CD4+ T cells, B cells, dendritic cells, neutrophils, and macrophages. CONCLUSIONS Our study may provide new insights into the optimal choice of immunotherapy and promising novel targets for therapeutic intervention in PAAD patients.
| S-EPMC8611937 | biostudies-literature
Project description:Recently, increasing evidence has indicated that the presence of tumor infiltrating immune cells has shown predictive significance for many solid tumors. Present study was performed to evaluate the predictive value of stromal tumor-infiltrating lymphocytes (TILs) for the presence of liver metastasis and overall survival in PDAC (pancreatic ductal adenocarcinoma) patients after complete resection and to explore the potential role of lymphocytes in PDAC. A total of 155 resectable patients with PDAC were enrolled in our study. Stromal TIL density was investigated in hematoxylin and eosin-stained sections of surgical specimens and scored. The effect and possible mechanism of lymphocytes on cancer cells was evaluated using co-culture techniques and ELISA test. Stromal TIL negative status (HR = 2.80, 95% CI 1.75-4.48, P < 0.01) was not only an independent predictor of worse OS (HR = 2.7, 95% CI 1.80-4.06, P = <0.01) but also a significant independent predictor of liver metastasis. Higher CEA (P = 0.01) or CA19-9 (P = 0.01) levels were associated with low stromal TIL density. Stromal TIL negative patients appeared to develop tumors with a higher CEA (P = 0.01), larger diameter (P = 0.05) and advanced stage (P = 0.02). The co-culture experiment suggests that lymphocytes can inhibit pancreatic cancer cell proliferation. Further ELISA and cell culture test indicate that lymphocytes may cause pancreatic cancer cells apoptosis through TNF-alpha secretion. Our data suggest a potential favorable role of stromal TILs in predicting liver metastasis and overall survival of patients with PDAC after complete resection. Lymphocytes may inhibit the growth of PDAC through TNF-alpha secretion, which suggest a potential therapeutic approach against PDAC.
| S-EPMC5902243 | biostudies-literature
Project description:Mucin 5AC (MUC5AC) glycoprotein plays a crucial role in carcinogenesis and drug sensitivity in pancreatic ductal adenocarcinoma (PDAC), both individually and in combination with other mucins. Its function and localization are glycoform-specific. The immature isoform (detected by the CLH2 monoclonal antibody, or mab) is usually in the perinuclear (cytoplasmic) region, while the mature (45 M1, 2-11, Nd2) variants are in apical and extracellular regions. There is preclinical evidence suggesting that mature MUC5AC has prognostic and predictive (response to treatment) value. However, these findings were not validated in clinical studies. We propose a MUC5AC signature with three components of MUC5AC-localization, variant composition, and intensity-suggesting a reliable marker in combination of variants than with individual MUC5AC variants alone. We also postulate a theory to explain the occurrence of different MUC5AC variants in abnormal pancreatic lesions (benign, precancerous, and cancerous). We also analyzed the effect of mature MUC5AC on sensitivity to drugs often used in PDAC management, such as gemcitabine, 5-fluorouracil, oxaliplatin, irinotecan, cisplatin, and paclitaxel. We found preliminary evidence of its predictive value, but there is a need for large-scale studies to validate them.
| S-EPMC10178741 | biostudies-literature
Project description:Choline kinase alpha (CHKA) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKA in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKA expression and a good correlation between protein expression and sensitivity to MN58b, a CHKA inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKA knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKA inhibition and, in vitro, MN58b had synergistic effects with gemcitabine, 5-fluorouracil and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKA was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKA did not relate to survival, nuclear CHKA distribution was observed in 43% of samples and was associated with survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKA inhibitors, we cultured IMIM-PC-2 cells with continuous incremental concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified up-regulation of ABCB1 and ABCB4 multidrug resistance transporters and functional studies confirmed that their up-regulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKA inhibition merits further attention as a therapeutic option in patients with PDAC.
2017-08-11 | GSE60321 | GEO
Project description:Choline kinase α (CHKα) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKα in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKα expression, associated with differentiation. CHKα protein expression was directly correlated with sensitivity to MN58b, a CHKα inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKα knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKα inhibition and, in vitro, MN58b had additive or synergistic effects with gemcitabine, 5-fluorouracil, and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKα was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKα did not relate to survival, nuclear CHKα distribution was observed in 43% of samples and was associated with longer survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKα inhibitors, we cultured IMIM-PC-2 cells with increasingly higher concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified upregulation of ABCB1 and ABCB4 multidrug resistance transporters, and functional studies confirmed that their upregulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKα inhibition merits further attention as a therapeutic option in patients with PDAC and that expression levels may predict response.
2018-03-28 | GSE112335 | GEO
Project description:Pancreatic adenocarcinoma (PAAD) is a malignant tumor with high morbidity and mortality rates. The NT5DC family is an evolutionarily-conserved family of 5'-nucleosidases that catalyze the intracellular hydrolysis of nucleotides. Although the NT5DC family has been linked to the initiation and growth of several cancers, its function in PAAD remains unclear. A series of bioinformatic analyses was used to ascertain the expression, prognosis, gene changes, functional enrichment, and immune regulatory functions of the NT5DC family in PAAD. NT5C2 and NT5DC1/2 mRNA and protein levels are increased in PAAD. Furthermore, the high mRNA expressions of NT5C2, NT5DC2, and NT5DC4 indicate a poor prognosis in patients with PAAD. The enrichment of biological processes and gene expression in the NT5DC family in PAAD were investigated using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses. Further investigations into immune infiltration revealed a close relationship between NT5DC gene expression and immune cell infiltration. These findings provide new insights into the biological function and prognostic value of the NT5DC gene family in PAAD.
| S-EPMC10414034 | biostudies-literature
Project description:BackgroundPancreatic adenocarcinoma (PAAD) is one of the most aggressive malignancies with a very poor prognosis. Exploring more therapeutic targets and prognostic biomarkers is of great significance to improve the prognosis of PAAD patients. Increasing evidence supports that the speckled protein (SP) 100 family is associated with human cancer and immune disorders. However, the function of the SP100 family members in PAAD is still unclear.MethodsR, Cytoscape, cBioPortal, and other software and online databases were used to comprehensively analyze the expression characteristics, prognostic value, and oncogenic mechanism of the SP100 family in PAAD.ResultsThe high expression of SP100 family members in PAAD was significantly correlated with poor clinicopathological features and poor prognosis of PAAD patients. Mechanistically, TP53 mutations were significantly associated with the expression levels of the SP100 family members, which were significantly coexpressed with M6A methylation regulators and were activated in multiple oncogenic pathways, including the EMT pathways. Moreover, we found that their expression levels were significantly correlated with the sensitivity of multiple traditional chemotherapeutic drugs.ConclusionThe SP100 family is closely related to the occurrence and development of PAAD and can be used as a new biomarker and therapeutic target for patients with PAAD.
| S-EPMC10333092 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a dismal 5-year survival rate of less than 5%. The lack of specific symptoms at early tumor stages and the paucity of biomarkers contribute to the poor diagnosis of pancreatic ductal adenocarcinoma. To improve prognosis, a screening biomarker for early diagnosis of pancreatic cancer is in urgent need. We searched the databases of expression profiling by array on GEO, aiming at comparing gene expression profile of matched pairs of pancreatic tumor and adjacent non-tumor tissues, and we screen out 4 suitable series of gene expression microarray data ("GSE15471", "GSE18670", "GSE28735" and "GSE58561"). After carefully analyzing, 13 DEGs (MYOF, SLC6A6, S100P, HK2, IFI44L, OSBPL3, IGF2BP3, PDK4, IL1R2, ERO1A, EGLN3, PLAC8 and ACSL5) are significantly differentially expressed in four microarray databases in common. After analyzing mRNA expression data and clinical follow-up survey provided in the TCGA database and clinicopathological data of 137 pancreatic ductal adenocarcinoma patients, we carefully demonstrated that three of these differentially expressed genes (ERO1A, OSBPL3 and IFI44L) are correlated with poor prognosis of pancreatic ductal adenocarcinoma patients. In addition, we revealed that cell-matrix adhesion and extracellular matrix were top significantly regulated pathways in pancreatic ductal adenocarcinoma and depicted two protein-protein interactions networks of extracellular matrix related Genes which are dysregulated according to 4 gene expression microarray data mentioned above ("GSE15471", "GSE18670", "GSE28735" and "GSE58561"), hoping to shed light on the etiology of PDAC and mechanisms of drug resistance in PDAC in this study.
| S-EPMC5581051 | biostudies-literature