Dataset Information

Differential expression profile of CXC-receptor-2 ligands as potential biomarkers in pancreatic ductal adenocarcinoma.

ABSTRACT: The discovery of early detection markers of pancreatic cancer (PC) disease is highly warranted. We analyzed the expression profile of different CXC-receptor-2 (CXCR2) ligands in PC cases for the potential of biomarker candidates. Analysis of different PDAC microarray datasets with matched normal and pancreatic tumor samples and next-generation sequenced transcriptomics data using an online portal showed significantly high expression of CXCL-1, 3, 5, 6, 8 in the tumors of PC patients. High CXCL5 expression was correlated to poor PC patient survival. Interestingly, mRNA and protein expression analysis of human PC cell lines showed higher CXCL2, 3, and 5 expressions in cell lines derived from metastatic sites than primary tumors. Furthermore, we utilized immunohistochemistry (IHC) to evaluate the expression of CXCR2 ligands in the human PC tumors and observed positive staining for CXCL1, 3, and 8 with a higher average IHC composite score of CXCL3 in the PC tissue specimens than the normal pancreas. We also observed an increase in the expression of mouse CXCL1, 3, and 5 in the pre-cancerous lesions of tumors and metastasis tissues derived from the PDX-cre-LSL-Kras^G12D mouse model. Together, our data suggest that different CXCR2 ligands show the potential of being utilized as a diagnostic biomarker in PC patients.

SUBMITTER: Saxena S

PROVIDER: S-EPMC8822283 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Differential expression profile of CXC-receptor-2 ligands as potential biomarkers in pancreatic ductal adenocarcinoma.

Saxena Sugandha S Molczyk Caitlin C Purohit Abhilasha A Ehrhorn Evie E Goel Paran P Prajapati Dipakkumar R DR Atri Pranita P Kaur Sukhwinder S Grandgenett Paul M PM Hollingsworth Michael A MA Batra Surinder K SK Singh Rakesh K RK

American journal of cancer research 20220115 1

The discovery of early detection markers of pancreatic cancer (PC) disease is highly warranted. We analyzed the expression profile of different CXC-receptor-2 (CXCR2) ligands in PC cases for the potential of biomarker candidates. Analysis of different PDAC microarray datasets with matched normal and pancreatic tumor samples and next-generation sequenced transcriptomics data using an online portal showed significantly high expression of CXCL-1, 3, 5, 6, 8 in the tumors of PC patients. High CXCL5 ...[more]

PMID: 35141005

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest gastrointestinal cancers with a 5-year survival rate of less than 10%. Biomarkers for early PDAC detection are useful in treating patients with PDAC. Extracellular vesicles (EVs) are lipid-bound vesicles that are potential biomarkers of various diseases such as PDAC. In this study, we quantitatively measured the serum levels of EVs (CD63+-EVs) or platelet-derived EVs (CD41+- and CD61+-EVs) and evaluated their potential use as biomarkers of PDAC.MethodsWe measured the serum levels of CD63+-, CD41+-, CD61+-EVs using sandwich enzyme-linked immunosorbent assay based on Tim4 with specificity for phosphatidylserine on EVs in age- and sex-matched healthy controls (HCs, n = 39) and patients with PDAC (n = 39). We also examined the effect of tumor burden on the serum EV levels after surgical resection (n = 28). CA19-9, a clinical PDAC biomarker, was also measured for comparison.ResultsSerum levels of CD63+-EVs, CD41+-EVs, and CD61+-EVs were significantly increased in patients with PDAC compared to HCs. Receiver operating characteristic analysis revealed that CD63+-EVs exhibited the highest diagnostic performance to discriminate patients with PDAC from HCs (area under the curve (AUC): 0.846), which was comparable to CA19-9 (AUC: 0.842). CA19-9 showed lower AUC values in early stages (I-II, AUC: 0.814) than in late stages (III-IV, AUC: 0.883) PDAC. Conversely, CD63+-EVs, CD41+-EVs, and CD61+-EVs showed comparable AUCs between early- and late-stage PDAC. The combined use of CA19-9 and CD63+-EVs showed a higher diagnostic performance for early-stage PDAC (AUC: 0.903) than CA19-9. The serum levels of CD63+-EVs, CD41+-EVs, CD61+-EVs, and CA19-9 decreased significantly after surgical resection, demonstrating that EVs are increased in sera of patients depending on the tumor burden.ConclusionsThe serum levels of CD63+-EVs and platelet-derived EVs (CD41+-EVs, CD61+-EVs) are increased in patients with PDAC than HCs. Since CD63+-EVs showed a high AUC to discriminate patients with PDAC from HCs; they might be useful as potential biomarkers for PDAC.

Project description:BackgroundPancreatic cancer is one of the principal causes of tumor-related death worldwide. CXC chemokines, a subfamily of functional chemotactic peptides, affect the initiation of tumor cells and clinical outcomes in several human malignant tumors. However, the specific biological functions and clinical significance of CXC chemokines in pancreatic cancer have not been clarified.MethodsBioinformatics analysis tools and databases, including ONCOMINE, GEPIA2, the Human Protein Atlas, DAVID, GeneMANIA, cBioPortal, STRING, DGidb, MethSurv, TRRUST, SurvExpress, SurvivalMeth, and TIMER, were utilized to clarify the clinical significance and biological functions of CXC chemokine in pancreatic cancer.ResultsExcept for CXCL11/12, the transcriptional levels of other CXC chemokines in PAAD tissues were significantly elevated, and the expression level of CXCL16 was the highest among these CXC chemokines. Our findings also suggested that all of the CXC chemokines were linked to tumor-immune dysfunction involving the abundance of immune cell infiltration, and the Cox proportional hazard model confirmed that dendritic and CXCL3/5/7/8/11/17 were significantly associated with the clinical outcome of PAAD patients. Furthermore, increasing expressions of CXCL5/9/10/11/17 were related to unfavorable overall survival (OS), and only CXCL17 was a prognostic factor for disease-free survival (DFS) in PAAD patients. The expression pattern and prognostic power of CXC chemokines were further validated in the independent GSE62452 dataset. For the prognostic value of single CpG of DNA methylation of CXC chemokines in patients with PAAD, we identified 3 CpGs of CXCL1, 2 CpGs of CXCL2, 2 CpGs of CXCL3, 3 CpGs of CXCL4, 10 CpGs of CXCL5, 1 CpG of CXCL6, 1 CpG of CXCL7, 3 CpGs of CXCL12, 3 CpGs of CXCL14, and 5 CpGs of CXCL17 that were significantly associated with prognosis in PAAD patients. Moreover, the prognostic value of CXC chemokine signature in PAAD was explored and tested in two independent cohort, and results indicated that the patients in the low-risk group had a better OS compared with the high-risk group. Survival analysis of the DNA methylation of CXC chemokine signature demonstrated that PAAD patients in the high-risk group had longer survival times.ConclusionsThese findings reveal the novel insights into CXC chemokine expression and their biological functions in the pancreatic cancers, which might serve as accurate prognostic biomarkers and suitable immunotherapeutic targets for patients with pancreatic cancer.

Project description:Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR-155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the combination of miR-21, miR-155 and miR-216 would be best for detecting and screening PDAC with area under the curve (AUC) of 0.8667 (95% CI: 0.7722-0.9612) and a better balance of sensitivity and specificity (83.33% vs. 83.33%). Our data indicate that miRNAs could be extracted and detected from pancreatic juice and stool efficiently and reproducibly. MiR-21, miR-155 and miR-216 in stool have the potential of becoming biomarkers for screening PDAC.

Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal common cancer because of late diagnosis. Novel biomarkers for PDAC early detection are urgently needed. tRNA-derived small RNAs (tsRNAs) are novel small RNAs might serve as biomarkers for cancer diagnosis and participate in diverse physiological and pathological process. We investigated whether the expression of tsRNAs in serum could be a noninvasive method in the early detection of PDAC. Blood sample of PDAC patients and healthy controls were collected from Ruijin Hospital, Shanghai, China. Tumor and adjacent normal pancreas tissues were collected from 51 patients with PDAC undergoing therapeutic surgery. The testing cohort comprised 6 PDAC patients and 6 healthy controls and the expression of small RNAs in serum was analyzed by small RNA sequence. We verified the diagnostic performance of serum tsRNAs by qPCR in validation cohort including 110 PDAC patients and 100 healthy controls. Expression level of tsRNAs in tissue was also verified in another independent cohort including 51 tumor and 51 adjacent normal pancreas tissues. Unpaired t-test and paired t-test are used for comparing depending on whether the samples are paired. The predictive performance of tsRNAs was evaluated by Kaplan-Meier survival and receiver operating characteristic (ROC) curve. There were 45 tsRNAs expressed at remarkably higher levels, 6 tsRNAs expressed at lower levels in PDAC patients, respectively, compared with healthy volunteers. tsRNA-ValTAC-41, tsRNA-MetCAT-37 and tsRNA-ThrTGT-23 expressed significant highly (P < 0.05) in serum of PDAC patients in validation cohort. tsRNA-ValTAC-41 or tsRNA-MetCAT-37 combined with CA19-9 could increase the AUC of PDAC prediction (AUC = 0.947 and 0.949 respectively), relative to CA19-9 test alone. Besides, patients with higher serum tsRNA-ValTAC-41 level showed shorter overall survival (OS). tsRNA-ValTAC-41 also expressed at remarkably higher level in tumor tissue, and it was obviously associated with tumor staging both in serum and tissue. We provide tsRNAs profiles observed by small RNA sequencing. The diagnostic accuracy of tsRNA-ValTAC-41 and tsRNA-MetCAT-37 in serum of PDAC patients were verified. Further studies for tsRNA-ValTAC-41 are needed to confirm the findings. These tsRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for PDAC diagnosis.

Dataset Information

Differential expression profile of CXC-receptor-2 ligands as potential biomarkers in pancreatic ductal adenocarcinoma.

Publications

Differential expression profile of CXC-receptor-2 ligands as potential biomarkers in pancreatic ductal adenocarcinoma.

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