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.