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Noteworthy prognostic value of phospholipase C delta genes in early stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy and potential molecular mechanisms.

ABSTRACT: The purpose of this investigation was to explore the prognostic value of phospholipase C delta (PLCD) genes in early stage pancreatic ductal adenocarcinoma (PDAC) and its potential molecular mechanisms. The prognostic value of PLCD genes in early stage PDAC was assessed using the Kaplan-Meier method and multivariate Cox proportional hazards regression model. Genome-wide correlation analysis was performed on PLCD3 to identify the highly correlated genes in the transcriptome. Then, PLCD3 and these correlated genes together underwent a bioinformatics analysis to elucidate the potential molecular biological functions of PLCD3 in PDAC. PLCD1 and PLCD3 are significantly overexpressed in PDAC. In PDAC patients, PLCD3 is overexpressed in certain groups of people with a history of alcoholism (P = .032). High expression of PLCD3 was found to be associated with lower overall survival (OS) of patients with early stage PDAC (P = .020; adjusted P = .016). A combination of PLCD3 and clinical variables was able to better predict the outcome of patients with early stage PDAC. These clinical variables are histological grade (P = .001; adjusted P = .001), targeted molecular therapy (P < .001; adjusted P < .001), radiation therapy (P = .002; adjusted P = .039), and residual resection (P = .001; adjusted P = .002). The bioinformatics analysis revealed that PLCD3 is associated with angiogenesis, intracellular signal transduction, and regulation of cell proliferation. In conclusion, PLCD3 may be a potential prognostic biomarker for early stage PDAC.

SUBMITTER: Zhou X

PROVIDER: S-EPMC6997088 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Noteworthy prognostic value of phospholipase C delta genes in early stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy and potential molecular mechanisms.

Zhou Xin X Liao Xiwen X Wang Xiangkun X Huang Ketuan K Yang Chengkun C Yu Tingdong T Han Chuangye C Zhu Guangzhi G Su Hao H Han Quanfa Q Chen Zijun Z Huang Jianlv J Gong Yizhen Y Ruan Guotian G Ye Xinping X Peng Tao T

Cancer medicine 20191206 3

The purpose of this investigation was to explore the prognostic value of phospholipase C delta (PLCD) genes in early stage pancreatic ductal adenocarcinoma (PDAC) and its potential molecular mechanisms. The prognostic value of PLCD genes in early stage PDAC was assessed using the Kaplan-Meier method and multivariate Cox proportional hazards regression model. Genome-wide correlation analysis was performed on PLCD3 to identify the highly correlated genes in the transcriptome. Then, PLCD3 and these ...[more]

PMID: 31808619

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Project description:Background: This study explored the prognostic significance of Glypican (GPC) family genes in patients with pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).Methods: A total of 112 PDAC patients from TCGA and 48 patients from GEO were included in the analysis. The relationship between overall survival and the expression of GPC family genes as well as basic clinical characteristics was analyzed using the Kaplan-Meier method with the log-rank test. Joint effects survival analysis was performed to further examine the relationship between GPC genes and prognosis. A prognosis nomogram was established based on clinical characteristics and prognosis-related genes. Prognosis-related genes were investigated by genome-wide co-expression analysis and gene set enrichment analysis (GSEA) was carried out to identify potential mechanisms of these genes affecting prognosis.Results: In TCGA database, high expression of GPC2, GPC3, and GPC5 was significantly associated with favorable survival (log-rank P?=?0.031, 0.021, and 0.028, respectively; adjusted P value?=?0.005, 0.022, and 0.020, respectively), and joint effects analysis of these genes was effective for prognosis prediction. The prognosis nomogram was applied to predict the survival probability using the total scores calculated. Genome-wide co-expression and GSEA analysis suggested that the GPC2 may affect prognosis through sequence-specific DNA binding, protein transport, cell differentiation and oncogenic signatures (KRAS, RAF, STK33, and VEGFA). GPC3 may be related to cell adhesion, angiogenesis, inflammatory response, signaling pathways like Ras, Rap1, PI3K-Akt, chemokine, GPCR, and signatures like cyclin D1, p53, PTEN. GPC5 may be involved in transcription factor complex, TFRC1, oncogenic signatures (HOXA9 and BMI1), gene methylation, phospholipid metabolic process, glycerophospholipid metabolism, cell cycle, and EGFR pathway.Conclusion: GPC2, GPC3, and GPC5 expression may serve as prognostic indicators in PDAC, and combination of these genes showed a higher efficiency for prognosis prediction.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.

Dataset Information

Noteworthy prognostic value of phospholipase C delta genes in early stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy and potential molecular mechanisms.

Publications

Noteworthy prognostic value of phospholipase C delta genes in early stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy and potential molecular mechanisms.

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