RESUMO
Recent studies have indicated that platelets may play a role in the advancement of pancreatic cancer by supporting tumor growth and increasing resistance to chemotherapy. This study aims to develop a prognostic model for pancreatic cancer using a platelet-related gene risk score. Prognostic platelet-related genes (PRGs) were identified from public databases and analyzed using cluster analysis. We investigated the microenvironment signatures and gene mutation patterns across different PRG-based molecular subtypes of pancreatic cancer. A prognostic model based on PRGs was developed using LASSO-Cox Regression Analysis. Additionally, we examined the correlation between the risk score and tumor clinical characteristics, as well as drug sensitivity. Two molecular subtypes, cluster C1 and C2, were identified. Cluster C2 was associated with a poorer prognosis compared to Cluster C1. The C1 group exhibited higher scores for activated CD8+ T cells, central memory CD4+ T cells, and natural killer T cells. The C2 group demonstrated a higher frequency of gene mutations. We established and validated a novel prognostic prediction model and platelet-related gene risk score for pancreatic cancer. The risk score was positively correlated with T stage, N stage, and tumor grade, and it presented a significant prognostic value compared to other clinical factors. In conclusion, a novel prognostic prediction model focusing on platelet involvement in pancreatic cancer has been developed, offering potential benefits for future drug therapies and clinical prognostic assessments.
RESUMO
BACKGROUND: Epithelial-mesenchymal transition of tubular epithelial cells, which is characterized by a loss of epithelial cell characteristics and a gain of ECM-producing myofibroblast characteristics, is an essential mechanism that is involved in tubulointerstitial fibrosis, an important component of the renal injury that is associated with diabetic nephropathy. Under diabetic conditions, p38 MAPK activation has been reported in glomeruli and mesangial cells; however, studies on p38 MAPK in TECs are lacking. In this study, the role of p38 MAPK in AP-1 activation and in the EMT in the human proximal tubular epithelial cell line (HK-2) under high glucose concentration conditions is investigated. METHODOLOGY/PRINCIPAL FINDINGS: A vector for small interfering RNA that targets p38 MAPK was constructed; the cells were then either transfected with p38 siRNA or pretreated with a chemical inhibitor of AP-1 and incubated with low glucose plus TGF-ß1 or high glucose for 48 h. Cells that were not transfected or pretreated and were exposed to low glucose with or without TGF-ß1 or high glucose for 48 h were considered to be the controls. We found that high glucose induced an increase in TGF-ß1. And high glucose-induced p38 MAPK activation was inhibited by p38 siRNA (P<0.05). A significant decline in E-cadherin and CK expression and a notable increase in vimentin and α-SMA were detected when exposed to low glucose with TGF-ß1 or high glucose, and a significant raise of secreted fibronectin were detected when exposed to high glucose; whereas these changes were reversed when the cells were treated with p38 siRNA or AP-1 inhibitor (P<0.05). AP-1 activity levels and Snail expression were up-regulated under high glucose conditions but were markedly down-regulated through knockdown of p38 MAPK with p38 siRNA or pretreatment with AP-1 inhibitor (P<0.05). CONCLUSION: This study suggests that p38 MAPK may play an important role in the high glucose-induced EMT by activating AP-1 in tubular epithelial cells.
