DPP6 and MFAP5 are associated with immune infiltration as diagnostic biomarkers in distinguishing uterine leiomyosarcoma from leiomyoma

Abstract

ObjectiveUterine leiomyosarcoma (ULMS) is the most common subtype of uterine sarcoma and is difficult to discern from uterine leiomyoma (ULM) preoperatively. The aim of the study was to determine the potential and significance of immune-related diagnostic biomarkers in distinguishing ULMS from ULM.MethodsTwo public gene expression profiles (GSE36610 and GSE64763) from the GEO datasets containing ULMS and ULM samples were downloaded. Differentially expressed genes (DEGs) were selected and determined among 37 ULMS and 25 ULM control samples. The DEGs were used for Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Disease Ontology (DO) enrichment analyses as well as gene set enrichment analysis (GSEA). The candidate biomarkers were identified by least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) analyses. The receiver operating characteristic curve (ROC) was applied to evaluate diagnostic ability. For further confirmation, the biomarker expression levels and diagnostic value in ULMS were verified in the GSE9511 and GSE68295 datasets (12 ULMS and 10 ULM), and validated by immunohistochemistry (IHC). The CIBERSORT algorithm was used to calculate the compositional patterns of 22 types of immune cells in ULMS.ResultIn total, 55 DEGs were recognized via GO analysis, and KEGG analyses revealed that the DEGs were enriched in nuclear division, and cell cycle. The recognized DEGs were primarily implicated in non−small cell lung carcinoma and breast carcinoma. Gene sets related to the cell cycle and DNA replication were activated in ULMS. DPP6 and MFAP5 were distinguished as diagnostic biomarkers of ULMS (AUC = 0.957, AUC = 0.899, respectively), and they were verified in the GSE9511 and GSE68295 datasets (AUC = 0.983, AUC = 0.942, respectively). The low expression of DPP6 and MFAP5 were associated with ULMS. In addition, the analysis of the immune microenvironment indicated that resting mast cells were positively correlated with DPP6 and MFAP5 expression and that eosinophils and M0 macrophages were negatively correlated with DPP6 expression (P<0.05).ConclusionThese findings indicated that DPP6 and MFAP5 are diagnostic biomarkers of ULMS, thereby offering a novel perspective for future studies on the occurrence, function and molecular mechanisms of ULMS.

Microfibril-associated protein 5 and the regulation of skin scar formation

“…MFAP5 was also expressed in keloids with primarily dermal and epidermal staining. Our staining results in wound, keloid, and normal skin tissue coincide with previous work studying expression patterns of MFAP5 in various cancers and the predicted locations by Human Protein Atlas (proteinatlas.org), which also suggests that fibroblasts are a major source of MFAP5 15,19,22,33,[53][54][55][56] . Future studies involving co-staining of MFAP5 with a cytoplasmic marker, such as vimentin, which also functions as a fibroblast marker, could be performed to determine if MFAP5 is also found intracellularly in fibroblasts of unwounded NS and wound tissue.…”

Potential Markers to Differentiate Uterine Leiomyosarcomas from Leiomyomas

“…For example, the proportion of macrophage M0 was notably higher in uterine leiomyosarcomas than in leiomyomas, and DPP6 was negatively related to M0 macrophages. Additionally, MFAP5 was positively related to resting mast cells, and the ratio of resting mast cells was significantly higher in ULM than in ULMS 34 . Therefore, the association of DPP6 and MFAP5 with immune cells can speculate that they may have an impact on immune-related pathways that influence the development and incidence of ULMS.…”

“…Furthermore, MFAP5, an extracellular matrix (ECM) glycoprotein, is implicated in cell survival, elastinogenesis, and signaling during microfibril construction 33 . Ke et al found that DPP6 and MFAP5 were expressed at significantly lower levels in ULMS than in ULM, and the area under the ROC curve (AUC) determined that DPP6 and MFAP5 had the diagnostic ability to distinguish ULMS from ULM (AUC values were 0.957 and 0.899, respectively) 34 . Studies have shown that the immune cell components of ULM and ULMS are different, and DPP6 and MFAP5 are also associated to infiltrating immune cells 34 , 35 .…”

“…Ke et al found that DPP6 and MFAP5 were expressed at significantly lower levels in ULMS than in ULM, and the area under the ROC curve (AUC) determined that DPP6 and MFAP5 had the diagnostic ability to distinguish ULMS from ULM (AUC values were 0.957 and 0.899, respectively) 34 . Studies have shown that the immune cell components of ULM and ULMS are different, and DPP6 and MFAP5 are also associated to infiltrating immune cells 34 , 35 . DPP6 was positively correlated with some immune cells that were more abundant in ULM and negatively correlated with some immune cells that were more abundant in ULMS.…”

Identification and validation of feature genes associated with M1 macrophages in preeclampsia

“…MFAP5 has been closely related to the progression of gynecological diseases, such as breast cancer, ovarian cancer, cervical cancer, and uterine tumors. However, there is no report on the role of MFAP5 in PE [29][30][31][32]. Recent studies suggest that impaired remodeling of uterine spiral arteries due to inadequate infiltration of the maternal decidua and myometrium could be critical in the early stages of the development of PE.…”