Abstract:Background: Accumulating evidence shows that the elevated expression of DCBLD2 (discoidin, CUB and LCCL domain-containing protein 2) is associated with unfavorable prognosis of various cancers. However, the correlation of DCBLD2 expression value with the diagnosis and prognosis of pancreatic ductal adenocarcinoma (PDAC) has not yet been elucidated. Methods: Univariate Cox regression analysis was used to screen robust survival-related genes. Expression pattern of selected genes was investigated in PDAC tissues … Show more
“…Previous work demonstrated that the SEMA4B and DCBLD2 interaction is involved in the regulation of the motility of lung cancer cell lines [ 14 ]. In addition, a recent study using PDAC cohorts reported that DCBLD2 was associated with poor survival in PDAC [ 15 ]. Fig.…”
Cell-to-cell interactions (CCIs) through ligand-receptor (LR) pairs in the tumor microenvironment underlie the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). However, there is scant knowledge of the association of CCIs with PDAC prognosis, which is critical to the identification of potential therapeutic candidates. Here, we sought to identify the LR pairs associated with PDAC patient prognosis by integrating survival analysis and single-cell CCI prediction. Via survival analysis using gene expression from cancer cohorts, we found 199 prognostic LR pairs. CCI prediction based on single-cell RNA-seq data revealed the enriched LR pairs associated with poor prognosis. Notably, the CCIs involved epithelial tumor cells, cancer-associated fibroblasts, and tumor-associated macrophages through integrin-related and
ANXA1
–
FPR
pairs. Finally, we determined that CCIs involving 33 poor-prognostic LR pairs were associated with tumor grade. Although the clinical implication of the set of LR pairs must be determined, our results may provide potential therapeutic targets in PDAC.
“…Previous work demonstrated that the SEMA4B and DCBLD2 interaction is involved in the regulation of the motility of lung cancer cell lines [ 14 ]. In addition, a recent study using PDAC cohorts reported that DCBLD2 was associated with poor survival in PDAC [ 15 ]. Fig.…”
Cell-to-cell interactions (CCIs) through ligand-receptor (LR) pairs in the tumor microenvironment underlie the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). However, there is scant knowledge of the association of CCIs with PDAC prognosis, which is critical to the identification of potential therapeutic candidates. Here, we sought to identify the LR pairs associated with PDAC patient prognosis by integrating survival analysis and single-cell CCI prediction. Via survival analysis using gene expression from cancer cohorts, we found 199 prognostic LR pairs. CCI prediction based on single-cell RNA-seq data revealed the enriched LR pairs associated with poor prognosis. Notably, the CCIs involved epithelial tumor cells, cancer-associated fibroblasts, and tumor-associated macrophages through integrin-related and
ANXA1
–
FPR
pairs. Finally, we determined that CCIs involving 33 poor-prognostic LR pairs were associated with tumor grade. Although the clinical implication of the set of LR pairs must be determined, our results may provide potential therapeutic targets in PDAC.
“…Parameswaran et al demonstrated that FAM83A overexpression promotes tumor progression through the MEK-ERK signaling pathway in PDAC (56). DCBLD2 and DSG were identified as unfavorable prognostic biomarkers in PDAC (57,58). Notably, it has been reported that FOXM1 is overexpressed in hypoxic cancer cells, which is mediated by HIF-1 (59) et al also demonstrated that FOXM1 impelled the Warburg effect and tumor progression in PDAC through transcriptional modulation of LDHA expression, indicating that FOXM1 is a HIF-1 target affecting PDAC metabolism and progression (60).…”
Section: Discussionmentioning
confidence: 99%
“…Parameswaran et al demonstrated that FAM83A overexpression promotes tumor progression through the MEK-ERK signaling pathway in PDAC ( 56 ). DCBLD2 and DSG were identified as unfavorable prognostic biomarkers in PDAC ( 57 , 58 ). Notably, it has been reported that FOXM1 is overexpressed in hypoxic cancer cells, which is mediated by HIF-1 ( 59 ).…”
Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic and desmoplastic tumor microenvironment (TME), leading to treatment failure. We aimed to develop a prognostic classifier to evaluate hypoxia status and hypoxia-related molecular characteristics of PDAC. In this study, we classified PDAC into three clusters based on 16 known hypoxia-inducible factor 1 (HIF-1)-related genes. Nine differentially expressed genes were identified to construct an HIF-1 score system, whose predictive efficacy was evaluated. Furthermore, we investigated oncogenic pathways and immune-cell infiltration status of PDAC with different scores. The C-index of the HIF-1score system for OS prediction in the meta-PDAC cohort and the other two validation cohorts were 0.67, 0.63, and 0.65, respectively, indicating that it had a good predictive value for patient survival. Furthermore, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve of the HIF-1α score system for predicting 1-, 3-, and 4-year OS indicated the HIF-1α score system had an optimal discrimination of prognostic prediction for PDAC. Importantly, our model showed superior predictive ability compared to previous hypoxia signatures. We also classified PDAC into HIF-1 scores of low, medium, and high groups. Then, we found high enrichment of glycolysis, mTORC1 signaling, and MYC signaling in the HIF-1 score high group, whereas the cGMP metabolic process was activated in the low score group. Of note, analysis of public datasets and our own dataset showed a high HIF-1 score was associated with high immunosuppressive TME, evidenced by fewer infiltrated CD8+ T cells, B cells, and type 1 T-helper cells and reduced cytolytic activity of CD8+ T cells. In summary, we established a specific HIF-1 score system to discriminate PDAC with various hypoxia statuses and immune microenvironments. For highly hypoxic and immunosuppressive tumors, a combination treatment strategy should be considered in the future.
“…Reported literature has revealed that DCBLD2 influences the emergence and progression of multiple diseases, including cancer ( Kikuta et al, 2017 ; He et al, 2020 ; Alhamoudi et al, 2021 ; Coppo et al, 2021 ; Feng et al, 2021 ). Moreover, DCBLD2 has been found to interact with the receptor tyrosine kinases EGFR, VEGFR, PDGFR, and INSR ( Nie et al, 2013 ; Feng et al, 2014 ; Schmoker et al, 2019 ; Schmoker et al, 2020 ).…”
Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2) is a two-domain transmembrane protein-coding gene located on chromosome 3, the protein expressed by which acts as the membrane receptor of semaphorin and vascular endothelial growth factor during the development of axons and blood vessels. Although several research evidences at the cellular and clinical levels have associated DCBLD2 with tumorigenesis, nothing is known regarding this gene from a pan-cancer standpoint. In this study, we systematically analyzed the influence of DCBLD2 on prognosis, cancer staging, immune characteristics, and drug sensitivity in a variety of cancers based on a unified and standardized pan-cancer dataset. In addition, we performed GO enrichment analyses and KEGG analyses of DCBLD2-related genes and DCBLD2-binding proteins. Our results showed that DCBLD2 is a potential oncogenic, immunological as well as a prognostic biomarker in terms of pan-cancer, and is expected to contribute to the improvement of tumor prognosis and the development of targeted therapy.
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