Diverse roles of SERPINE1 in regulating cellular proliferation and invasion

SERPINE1 is involved in various biological processes, but its roles in promoting or suppressing tumorigenesis remain controversial. To understand the underlying mechanisms, we focused on the effects of SERPINE1 downregulation on cell phenotypes, particularly proliferation and invasion, across three types of tumors. High SERPINE1 levels in breast cancer (BRCA) and low-grade glioma (LGG) were associated with poor prognosis. In contrast, elevated SERPINE1 levels in skin cutaneous melanoma (SKCM) correlated with better outcomes. SERPINE1 knockdown resulted in increased xenograft growth in the melanoma cell line C918. This was characterized by the promotion of the cell cycle through the modulation of minichromosome maintenance protein expression and the activity of p53 and SMAD3. In breast cancer cells (MDA-MB-231) with SERPINE1 knockdown, there was decreased xenograft growth and cell proliferation, attributed to a reduction in the uPAR-mediated ERK/p38 activity ratio. With SERPINE1 knockdown, both C918 and MDA-MB-231 cells demonstrated reduced invasion capabilities, decreased matrix metalloproteinase (MMP) activity, and reduced lung metastasis. In low-grade glioma cells (H4), SERPINE1 knockdown led to decreased cell proliferation due to a reduction in the HSP90-mediated ERK/p38 activity ratio. However, it increased invasion and MMP activity, particularly of MMP-1, regulated by the HSP90-p38 axis. Collectively, our findings reveal that SERPINE1 exerts diverse effects on cell proliferation and invasion through context-dependent mechanisms. These results suggest that targeting SERPINE1 may offer personalized therapeutic strategies to enhance treatment precision and reduce adverse effects. Overall design: RNA-seq profiling of MDA-MB-231, H4 and C918 cells and their stably knockdown derivatives (shSE1)

丝氨酸蛋白酶抑制蛋白E1（SERPINE1）参与多种生物学过程，但其在肿瘤发生发展中的促癌或抑癌作用仍存在争议。为阐明其潜在分子机制，本研究聚焦于SERPINE1下调对三种肿瘤细胞表型——尤其是增殖与侵袭能力——的影响。
乳腺癌（BRCA）与低级别胶质瘤（LGG）中SERPINE1高表达与不良预后显著相关；与之相反，皮肤黑色素瘤（SKCM）中SERPINE1高表达则与更佳的临床结局呈正相关。
敲低SERPINE1可促进黑色素瘤细胞系C918的异种移植瘤生长，其机制为通过调控微染色体维持蛋白（minichromosome maintenance protein）的表达水平及p53与SMAD3的活性，推动细胞周期进程。
在敲低SERPINE1的乳腺癌细胞MDA-MB-231中，异种移植瘤生长与细胞增殖能力均显著下降，该现象归因于uPAR介导的ERK/p38信号活性比值降低。
无论是C918还是MDA-MB-231细胞，敲低SERPINE1后其侵袭能力均减弱，基质金属蛋白酶（MMP）活性降低，且肺转移灶数量减少。
在低级别胶质瘤细胞H4中，敲低SERPINE1可通过降低HSP90介导的ERK/p38信号活性比值抑制细胞增殖；但与此同时，其侵袭能力与MMP活性（尤其是MMP-1）却显著增强，该调控过程由HSP90-p38信号轴介导。
综上，本研究揭示SERPINE1可通过情境依赖的分子机制，对细胞增殖与侵袭能力发挥多样化的调控作用。上述结果提示，靶向SERPINE1可为制定个性化肿瘤治疗策略提供依据，进而提升治疗精准度并降低不良反应。
实验整体设计：对MDA-MB-231、H4及C918细胞及其稳定敲低株（shSE1）开展RNA测序（RNA-seq）转录组分析。