Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Life Sci. 2024 Nov 15;357:123113. doi: 10.1016/j.lfs.2024.123113. Epub 2024 Oct 5.
The immunosuppressive tumour microenvironment (TME) plays a critical role in cancer progression and relapse by significantly influencing cancer pathogenesis through autocrine and paracrine signalling. Trefoil factor 3 (TFF3), a secreted protein, has been implicated in modulating the TME to promote cancer advancement. Herein, we investigated the potential association between TFF3 and key immunosuppressive TME components to distinguish a co-targetable oncotherapeutic strategy.
The TFF3-PVRL2 association were identified and investigated by integrating multiple bioinformatic-tools. The virtual compound screening for PVRL2 inhibitors was done with EasyVS. The TFF3-PVRL2 protein-level correlation was validated by immunoblotting, and the effectiveness of co-inhibiting TFF3 and PVRL2 was assessed using siRNA and AMPC (a TFF3 inhibitor).
Analysis of the TISIDB database revealed a positive correlation between TFF3 and PVRL2 mRNA levels across multiple cancer types. This correlation was confirmed at the protein level through immunoblot analysis. Further evaluation using TCGA pan-cancer datasets demonstrated that TFF3 and PVRL2 interact to establish an immunosuppressive TME, promoting cancer progression in BRCA, LUAD, PAAD, PRAD, and STAD. Enrichment analyses of positively correlated genes, PPI network hub proteins, and ceRNA networks involving TFF3 and PVRL2, conducted using LinkedOmics, STRING, and Cytoscape, provided insights into their potential co-functions in cancer. A cell-based assay was performed to evaluate the combined therapeutic efficacy of targeting both, TFF3 and PVRL2 and virtual screening identified potential drugs for inhibiting PVRL2.
PVRL2 has emerged as a promising immunoinhibitory target with significant associations with TFF3 and represents a key co-targetable molecule for effective oncotherapeutic strategies.
免疫抑制性肿瘤微环境（TME）通过自分泌和旁分泌信号显著影响癌症发病机制，在癌症进展和复发中发挥着关键作用。三叶因子 3（TFF3）是一种分泌蛋白，已被证明可以调节 TME 以促进癌症进展。在此，我们研究了 TFF3 与关键免疫抑制性 TME 成分之间的潜在关联，以区分一种可共同靶向的肿瘤治疗策略。
通过整合多种生物信息学工具，确定并研究了 TFF3-PVRL2 的关联。使用 EasyVS 对 PVRL2 抑制剂进行虚拟化合物筛选。通过免疫印迹验证 TFF3-PVRL2 蛋白水平的相关性，并使用 siRNA 和 AMPC（TFF3 抑制剂）评估共同抑制 TFF3 和 PVRL2 的效果。
对 TISIDB 数据库的分析显示，多种癌症类型中 TFF3 和 PVRL2 的 mRNA 水平呈正相关。通过免疫印迹分析在蛋白水平上证实了这一点。进一步使用 TCGA 泛癌数据集进行评估表明，TFF3 和 PVRL2 相互作用，建立了一个免疫抑制性 TME，促进了 BRCA、LUAD、PAAD、PRAD 和 STAD 中的癌症进展。使用 LinkedOmics、STRING 和 Cytoscape 进行的与 TFF3 和 PVRL2 相关的正相关基因、PPI 网络枢纽蛋白和 ceRNA 网络的富集分析，提供了它们在癌症中潜在共同功能的见解。进行了一项基于细胞的测定，以评估同时靶向 TFF3 和 PVRL2 的联合治疗效果，并通过虚拟筛选确定了潜在的抑制 PVRL2 的药物。
PVRL2 已成为一种有前途的免疫抑制性靶标，与 TFF3 具有显著相关性，是有效肿瘤治疗策略的关键共同靶标。
