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. 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. 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.

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3 类信号蛋白作为癌症治疗靶点的泛癌研究

信号蛋白最初被定性为轴突引导因子，但也被认为在多种生理和发育功能中发挥关键作用，包括免疫反应的调节、血管生成、器官形成和多种癌症的病因学。此外，它们在免疫和肿瘤微环境调节方面的贡献日益得到认可。在这里，我们对 3 类信号蛋白（脊椎动物信号蛋白中唯一的分泌基因家族）的表达谱及其与患者生存的关系进行了全面分析。我们还通过泛癌研究将它们的作用与免疫亚型、肿瘤微环境和药物敏感性联系起来。使用 TCGA 泛癌数据研究了 31 种癌症类型中 3 类信号蛋白 (SEMA3) 的表达谱及其与患者生存和肿瘤微环境的关联。SEMA3家族的表达在不同的癌症类型中存在差异，并且具有显着的癌间和癌内异质性。总的来说，我们的结果表明SEMA3A、SEMA3C和SEMA3F在癌细胞中主要上调，而其余SEMA3在测试的肿瘤中主要下调。SEMA3 家族成员的表达通常与患者的总生存期相关。然而，关联的方向因所查询的特定 SEMA3 同工型和所测试的特定癌症类型而异。更具体地说，SEMA3A和SEMA3E主要与生存预后不良相关，而SEMA3G通常与生存优势相关。其余 SEMA3 表现出生存优势或劣势，具体取决于癌症类型。此外，所有SEMA3基因均与免疫浸润亚型显着相关，并且还与基质细胞浸润水平和肿瘤细胞干性有不同程度的相关性。最后，我们的研究表明SEMA3基因，特别是SEMA3C和SEMA3F可能有助于药物诱导的癌细胞耐药性。我们对 3 类信号蛋白基因表达及其与免疫浸润、肿瘤微环境和癌症患者结果的关联进行了系统分析，强调需要将每个 SEMA3 成员作为每种特定癌症类型中的独立实体进行研究。我们的研究还验证了 3 类信号蛋白信号作为癌症有希望的治疗靶点的鉴定，尽管仍需要进一步的实验室验证。