ABSTRACT
BACKGROUND: Tumor initiation and progression are closely associated with glycosylation. However, glycosylated molecules have not been the subject of extensive studies as prognostic markers for pancreatic cancer. The objectives of this study were to identify glycosylation-related genes in pancreatic cancer and use them to construct reliable prognostic models. MATERIALS AND METHODS: The Cancer Genome Atlas and Gene Expression Omnibus databases were used to assess the differential expression of glycosylation-related genes; four clusters were identified based on consistent clustering analysis. Kaplan-Meier analyses identified three glycosylation-related genes associated with overall survival. LASSO analysis was then performed on The Cancer Genome Atlas and International Cancer Genome Consortium databases to identify glycosylation-related signatures. We identified 12 GRGs differently expressed in pancreatic cancer and selected three genes (SEL1L, TUBA1C, and SDC1) to build a prognostic model. Thereafter, patients were divided into high and low-risk groups. Eventually, we performed Quantitative real-time PCR (qRT-PCR) to validate the signature. RESULTS: Clinical outcomes were significantly poorer in the high-risk group than in the low-risk group. There were also significant correlations between the high-risk group and several risk factors, including no-smoking history, drinking history, radiotherapy history, and lower tumor grade. Furthermore, the high-risk group had a higher proportion of immune cells. Eventually, three glycosylation-related genes were validated in human PC cell lines. CONCLUSION: This study identified the glycosylation-related signature for pancreatic cancer. It is an effective predictor of survival and can guide treatment decisions.
Subject(s)
Pancreatic Neoplasms , Humans , Glycosylation , Pancreatic Neoplasms/genetics , Cell Line , Cell Transformation, Neoplastic , Cluster Analysis , Prognosis , ProteinsABSTRACT
The present study examined the role of a polysaccharide (LSP, 25 and 100⯵g/ml) from the fruiting bodies of Lepista sordid on the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO) in HepG2 cells, and the possible mechanism of action. IDO expression and kynurenine production from LSP-treated HepG2 cells following IFN-γ stimulation were dramatically inhibited by LSP treatment. In line with this, the medium of HepG2 cells pretreated with LSP improved the survival rate of primary CD4+ and CD8+ T cells as compared with IFN-γ-treated control cells. Moreover, tyrosine 701 and serine 727 phosphorylation of STAT1 were dramatically reduced by LSP pretreatment in IFN-γ-stimulated HepG2 cells. Furthermore phosphorylation of JAK-1 and JAK-2 was also inhibited by LSP. Additionally, two IDO promoters (GAS and ISRE) were inhibited in cells pretreated with LSP prior to IFN-γ exposure. These findings suggest that LSP exerts antitumor effects on HepG2 cells by inhibiting IDO via JAK-PKC-δ-STAT1 signaling pathway.
Subject(s)
Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Janus Kinase 1/antagonists & inhibitors , Polysaccharides/pharmacology , Protein Kinase C-delta/antagonists & inhibitors , STAT1 Transcription Factor/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Fruiting Bodies, Fungal/chemistry , Hep G2 Cells , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Janus Kinase 1/metabolism , Lepisma/chemistry , Polysaccharides/chemistry , Polysaccharides/isolation & purification , Protein Kinase C-delta/metabolism , STAT1 Transcription Factor/metabolism , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
Pachymic acid (PA) is a lanostane type triterpenoid isolated from Poria cocos, which possesses an anti-tumor effect in breast cancer, prostate cancer, lung cancer, and bladder cancer cells. In this study, we investigated the effect of PA on the growth and apoptosis of human immortalized cell line (HOS) and primary osteosarcoma cells by a Cell Counting Kit-8 (CCK-8) and Annexin V and propidium iodide (PI) staining, respectively. Western blot was used to measure the expression of cleaved Caspase 3, PTEN, and AKT, as well as the AKT phosphorylation. The Caspase 3 activity was determined using the Caspase-3 Colorimetric Assay Kit. From the results, PA significantly reduced cell proliferation in a concentration- and time-dependent manner. PA also induced cell apoptosis in a dose-dependent fashion. PA treatment led to increased Caspase 3 activation and PTEN expression, as well as reduced AKT phosphorylation. Moreover, Ac-DEVD-CHO (a Caspase 3/7 inhibitor) pre-treatment or PTEN knockdown partially blocked the effects of PA on cell proliferation and apoptosis. Caspase 3/7 inhibitor had an additive effect with PTEN knockdown. Collectively, our results suggested that induction of apoptosis by PA was mediated in part by PTEN/AKT signaling and Caspase 3/7 activity. This study provides evidence that PA might be useful in the treatment of human osteosarcoma.
