A pan-cancer study of class-3 semaphorins as therapeutic targets in cancer

Abstract

Background: Initially characterized as axon guidance factors, semaphorins also have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer. Moreover, their contribution in immunity and the regulation of tumour microenvironment is becoming increasingly recognized. Here, we provide a comprehensive analysis of class-3 semaphorins, the only secreted family of genes among veterbrate semaphorins, in terms of their expression profiles and their association with patient survival. We also relate their role with immune subtypes, tumour microenvironment, and drug sensitivity using a pan-cancer study. Results: Expression profiles of class-3 semaphorins (SEMA3s) and their association with patient survival and tumour microenvironment were studied in 31 cancer types using the TCGA pan-cancer data. The expression of SEMA3 family varies in different cancer types with striking inter-and intra-cancer heterogeneity. In general, our results show that SEMA3A, SEMA3C, and SEMA3F are primarily upregulated in cancer cells, while the rest of SEMA3s are mainly down-regulated in the tested tumours. The expression of SEMA3 family members was frequently associated with patient overall survival. However, the direction of the association varied with regards to the particular SEMA3 isoform queried and the specific cancer type tested. More specifically, SEMA3A and SEMA3E primarily associate with a poor prognosis of survival, while SEMA3G typically associates with survival advantage. The rest of SEMA3s show either survival advantage or disadvantage dependent on cancer type. In addition, all SEMA3 genes show significant association with immune infiltrate subtypes, and they also correlate with level of stromal cell infiltration and tumour cell stemness with various degrees. Finally, our study revealed that SEMA3 genes, especially SEMA3C and SEMA3F may contribute to drug induced cancer cell resistance. Conclusions: Our systematic analysis of class-3 semaphorin gene expression and their association with immune infiltrates, tumour microenvironment and cancer patient outcomes highlights the need to study each SEMA3 member as a separate entity within each specific cancer type. Also our study validated the identification of class-3 semaphorin signals as promising therapeutic targets in cancer although further laboratory validation still needed.

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

“…Our previous study showed that SEMA3s were generally correlated with patient overall survival [11]. Because the functions of SEMA3s are attributed to their receptors, we further tested whether the Figure 2.…”

“…Our previous study showed that SEMA3s were generally correlated with patient overall survival [11]. Because the functions of SEMA3s are attributed to their receptors, we further tested whether the expression of SEMA3 receptors could also predict patient survival outcomes, including overall survival (OS) and progression free interval (PFI).…”

Markers of Angiogenesis, Lymphangiogenesis, and Epithelial–Mesenchymal Transition (Plasticity) in CIN and Early Invasive Carcinoma of the Cervix: Exploring Putative Molecular Mechanisms Involved in Early Tumor Invasion

“…Indeed, while class 4 semaphorins are characterized mostly as pro-tumorigenic and proangiogenic SEMAs, class 3 semaphorins, with a few exceptions, are regarded as endogenous inhibitors of (lymph-)angiogenesis [96,97]. From the TCGA pan-cancer data analysis, Zhang et al inferred that SEMA3B and SEMA3E were predominantly downregulated in cancer [98]. SEMA3E, altered by logFC of 4.8 in our study (Table S3), has been previously found to function as an inhibitor of tumor development, angiogenesis and metastasis (discussed in [97]).…”

A Methylation-Based Reclassification of Bladder Cancer Based on Immune Cell Genes

“…The differentiated phenotype was rapidly lost during cancer progression, and progenitor and stem-cell-like characteristics were acquired [ 102 ]. The DNA hypermethylation of those genes suppressed gene expression, which was significantly benefited by cancer cells.…”