Comprehensive analysis of UPK3B as a marker for prognosis and immunity in pancreatic adenocarcinoma

Abstract

The low immunogenicity of pancreatic cancer inhibits effective antitumor immune responses, primarily due to the immune evasion mediated by low expression of the major histocompatibility complex (MHC). Through comprehensive analysis, our study identifies UPK3B as a gene closely associated with low MHC expression and low immunogenicity in pancreatic cancer. UPK3B has been reported as a marker of primary mesothelial cells, mature epicardium and promotes extracellular matrix signaling. However, the role of UPK3B in pancreatic cancer remain unclear. We found that UPK3B is highly predictive of overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC) and is significantly related to clinical features, immune cell infiltration, and response to immune checkpoint inhibitor (ICI) therapy. Gene enrichment analysis revealed significant downregulation of immune regulatory and BCR signaling pathways in the UPK3B high-expression group. Additionally, UPK3B is positively correlated with immunosuppressive cells, suggesting that high UPK3B expression may inhibit antitumor immune responses by promoting low MHC expression. UPK3B is also positively correlated with immune checkpoints, indicating that tumors with high UPK3B expression may not benefit from ICI therapy. Therefore, UPK3B may serve as a novel biomarker and therapeutic target for pancreatic cancer.

Keywords: Biomarker; Immunosuppression; MHC; Pancreatic Cancer; Prognosis.

Fig. 1

Identification of hub genes. (A-C) UPK3B was selected as a hub gene. (D) Volcano plot of differential expression analysis in TCGA. (E) Results of Univariate Cox analysis for all genes. (F) Volcano plot of differential expression analysis in GSE132956.

Fig. 2

Immunohistochemistry images of UPK3B in pancreatic cancer. (A) The immunohistochemistry picture shows the UPK3B expression in pancreatic cancer. (B) The immunohistochemistry picture shows the UPK3B expression in normal pancreas tissue. (C) The bar chart shows the semi-quantification of UPK3B expression in normal pancreas tissue and pancreatic cancer.

Fig. 3

Clinical significance of UPK3B in pancreatic cancer patients. (A) UPK3B is highly expressed in pancreatitis and tumor samples. (B) UPK3B is highly expressed in high-grade pathological and advanced samples. (C, D) Patients with high UPK3B expression have worse overall survival (OS) and progression-free survival (PFS).

Fig. 4

GSEA enrichment analysis and immune infiltration analysis based on UPK3B. (A, B) Immune activation-related pathways are downregulated in the UPK3B high expression group. (C) The stromal and immune scores are lower in the UPK3B high expression group. (D, E) UPK3B expression is negatively correlated with immune-activated cells and positively correlated with immunosuppressive cells.

Fig. 5

Immunotherapy outcome prediction and validation. (A) Correlation analysis of UPK3B with immune checkpoints. (B) TIDE scoring based on UPK3B. (C) The prognostic significance of UPK3B was validated in three additional datasets. *p < 0.05;**p < 0.01;***p < 0.001.

Fig. 6

Validation of UPK3B in scRNA-seq. (A) UMAP dimensionality reduction plots for various cell types. (B) UPK3B expression in malignant cells. (C, D) KEGG and GO enrichment analysis results for marker genes in UPK3B-positive malignant cells. (E) GSEA results show that immune activation-related pathways are downregulated in UPK3B-positive malignant cells.

Fig. 7

Influence of UPK3B on the phenotypic characteristics of pancreatic cancer cells. (A) Protein expression of UPK3B in pancreatic cancer cells. (B) The protein expression of UPK3B decreases in Ascp- 1 and PANC1 cell lines following the silencing of UPK3B. (C, D) Cell proliferation decreases after transfection of si-UPK3B. (E-H) Cell invasion and migration are inhibited after transfection of si-UPK3B. (I, J) Inhibition of UPK3B increases the expression of MHC on the cell surface. (K) The expression of UPK3B decreases in KPC cell line following knockdown of UPK3B. (L) Gross appearance of the tumor in the orthotopic injection tumor model in the con, shUPK3B, ICB, and ICB + shUPK3B groups. (M-N) Quantitative analysis showed the volume and weight of the tumor. *p < 0.05;**p < 0.01;***p < 0.001.