Liu Hui-Long, Gao XiaoSheng, Yang WeiFeng, Li Wang-Lin
Department of Colorectal Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
Front Oncol. 2025 May 20;15:1585935. doi: 10.3389/fonc.2025.1585935. eCollection 2025.
Cell-cell crosstalk in the tumor microenvironment (TME) is crucial for cancer development and strongly correlates with clinical outcomes. Interpatient variability in tumor microenvironment composition and function poses ongoing challenges for personalized therapy selection, remaining a significant clinical problem. Serpin family E member 2 (SERPINE2) released from the tumor microenvironment exhibits significant regulatory functions in cancer progression but the role of SERPINE2 in the tumor microenvironment remains unclear. In this study, we want to investigate the potential mechanism of SERPINE2 in tumor microenvironment of colon cancer.
Bioinformatics analysis was used for exploring the mRNA expression level of SERPINE family in Pan-cancer, the prognostic significance of SERPINE family overexpression in four cancer types, the clinical relevance of SERPINE2 and the potential function of SERPINE2 in colorectal cancer. We conducted qRT-PCR, Western blot and ELISA to investigate the expression of SERPINE2. Additionally, Tissue chips, Transwell assays, Cell counting kit-8 assay, and co-culture system were used to evaluate the relationship between SERPINE2 and polarization of tumor-associated macrophages.
Based on public database screening, the SERPINE family genes were significantly upregulated in various cancers, and high expression of SERPINE family genes in colorectal cancer was closely associated with poor prognosis. Compared to other family members, SERPINE2 showed a high expression level and was closely related to clinical malignant progression of colon cancer patients. co-expression network analysis, KEGG and GO analysis revealed that SERPINE2 expression correlates with tumor immunoregulation, division and proliferation. Immune infiltration analysis indicated a significant positive correlation between SERPINE2 and M2 macrophage infiltration, and tissue chip confirmed the correlation between SERPINE2 expression in colon cancer tissues and macrophage infiltration. Cell co-culture experiments further demonstrated that SERPINE2 secreted by colon cancer cells can induce polarization of M2 macrophages. Next, the recombinant protein SERPINE2 was observed to stimulate macrophage polarization. We found macrophages induced by SERPINE2 in co-culture with cancer cells accelerated cancer cell proliferation and migration.
Our study demonstrates that tumor-secreted SERPINE2 mediates a positive feedback loop between tumor cells and M2 macrophages to accelerate cancer progression, suggesting SERPINE2 may be as a promising therapeutic target for colon cancer treatment.
肿瘤微环境（TME）中的细胞间串扰对于癌症发展至关重要，且与临床结果密切相关。肿瘤微环境组成和功能的患者间变异性给个性化治疗选择带来持续挑战，仍是一个重大临床问题。从肿瘤微环境中释放的丝氨酸蛋白酶抑制剂家族E成员2（SERPINE2）在癌症进展中表现出显著调节功能，但SERPINE2在肿瘤微环境中的作用仍不清楚。在本研究中，我们想探究SERPINE2在结肠癌肿瘤微环境中的潜在机制。
利用生物信息学分析来探索泛癌中SERPINE家族的mRNA表达水平、SERPINE家族过表达在四种癌症类型中的预后意义、SERPINE2的临床相关性以及SERPINE2在结直肠癌中的潜在功能。我们进行了qRT-PCR、蛋白质免疫印迹和酶联免疫吸附测定以研究SERPINE2的表达。此外，使用组织芯片、Transwell实验、细胞计数试剂盒 - 8实验和共培养系统来评估SERPINE2与肿瘤相关巨噬细胞极化之间的关系。
基于公共数据库筛选，SERPINE家族基因在各种癌症中显著上调，且结直肠癌中SERPINE家族基因的高表达与不良预后密切相关。与其他家族成员相比，SERPINE2表现出高表达水平，且与结肠癌患者的临床恶性进展密切相关。共表达网络分析、KEGG和GO分析表明SERPINE2表达与肿瘤免疫调节、分裂和增殖相关。免疫浸润分析表明SERPINE2与M2巨噬细胞浸润之间存在显著正相关，组织芯片证实结肠癌组织中SERPINE2表达与巨噬细胞浸润之间的相关性。细胞共培养实验进一步证明，结肠癌细胞分泌的SERPINE2可诱导M2巨噬细胞极化。接下来，观察到重组蛋白SERPINE2刺激巨噬细胞极化。我们发现与癌细胞共培养时由SERPINE2诱导的巨噬细胞加速了癌细胞的增殖和迁移。
我们的研究表明，肿瘤分泌的SERPINE2介导肿瘤细胞与M2巨噬细胞之间的正反馈回路以加速癌症进展，提示SERPINE2可能是结肠癌治疗的一个有前景的治疗靶点。
