Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms

Abstract

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.

GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma

“…GPCs include GPC1, GPC2, GPC3, GPC4, GPC5, and GPC6 [ 23 ]. GPC1 is upregulated in pancreatic cancer, esophageal cancer, and prostate cancer, and it promotes the proliferation and movement of esophageal cancer cells by PTEN/Akt/β-catenin pathway [ 24 , 25 , 26 ]. High levels of GPC3 in serum have been shown to be a marker for hepatoblastoma and hepatocellular carcinoma [ 26 , 27 ].…”

“…GPC1 is upregulated in pancreatic cancer, esophageal cancer, and prostate cancer, and it promotes the proliferation and movement of esophageal cancer cells by PTEN/Akt/β-catenin pathway [ 24 , 25 , 26 ]. High levels of GPC3 in serum have been shown to be a marker for hepatoblastoma and hepatocellular carcinoma [ 26 , 27 ]. Overexpression of GPC5 may accelerate the tumor progression of lymphoma and may enhance the interaction between Patched 1 and Hedgehog signaling in rhabdomyosarcoma [ 26 ].…”

“…High levels of GPC3 in serum have been shown to be a marker for hepatoblastoma and hepatocellular carcinoma [ 26 , 27 ]. Overexpression of GPC5 may accelerate the tumor progression of lymphoma and may enhance the interaction between Patched 1 and Hedgehog signaling in rhabdomyosarcoma [ 26 ]. GPC2 plays an important role in neural cell adhesion and neurite growth, and researchers have found that GPC2 is a powerful candidate target for immunotherapy in childhood cancer [ 28 ].…”

GPC2 Is a Potential Diagnostic, Immunological, and Prognostic Biomarker in Pan-Cancer

“…The GeneMANIA database (http://www.genemania.org) is a user-friendly website that can find functionally similar genes according to the given gene list based on a wealth of genomics and proteomics data (23). Through detection of similar gene functions in GeneMANIA, we identified genes whose expression patterns were similar to those of GPC2.…”

“…However, small-cell lung cancer and prostate cancer were discovered to have an upregulated expression ( 17 , 22 ). Moreover, experiences show that a high expression of GPC2 may lead to favorable prognosis in early pancreatic duct adenocarcinoma after pancreaticoduodenectomy ( 23 ). Generally, GPC2 has an effect on protein transduction, cell proliferation and differentiation, and oncogenic signatures ( 7 , 23 ).…”