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Diverse roles of SERPINE1 in regulating cellular proliferation and invasion

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300877 | GEO | 2025/07/03

REPOSITORIES: GEO

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Project description:The clinical outcomes of hepatocellular carcinoma (HCC) remain dismal. Elucidating the molecular mechanisms for the progression of aggressive HCC holds the promise for developing novel intervention strategies. The transactivation response element RNA-binding protein (TRBP/TARBP2), a key component of microRNA (miRNA) processing and maturation machinery has exhibited to play conflicting roles in tumor development and progression. We sought to investigate the expression of TARBP2 in HCC using well-characterized HCC cell lines, patient-derived tissues and blood samples. Additionally, the potential prognostic and diagnostic value of TARBP2 in HCC were analyzed using Kaplan-Meier plots and ROC curve. Cell counting kit‐8 (CCK‐8), wound healing and transwell assays examined the ability of TARBP2 to induce cell proliferation, migration, and invasion in HCC cell lines. RNA sequencing was applied to identify the downstream elements of TARBP2. The interaction of potential targets of TARBP2, miR‐145 and serpin family E member 1 (SERPINE1), was assessed using luciferase reporter assay. TARBP2 expression was down-regulated in HCC cell lines relative to normal hepatocyte cells, with a similar pattern further confirmed in tissue and blood samples. Notably, the loss of TARBP2 was demonstrated to promote proliferation, migration, and invasion in HCC cell lines. Interestingly, the reduction of TARBP2 was shown to result in the upregulation of SERPINE1, also known as plasminogen activator inhibitor (PAI-1), which is a vital gene of the HIF-1 signaling pathway. Knockdown of SERPINE1 rescued the TARBP2-lost phenotype. Moreover, TARBP2 depletion induced the upregulation of SERPINE1 through reducing the processing of miR-145, which directly targets SERPINE1. Finally, overexpression of miR-145 repressed SERPINE1 and rescued the functions in sh-TARBP2 HCC cells. Our findings underscore a linear TARBP2-miR-145-SERPINE1 pathway that drives HCC progression, with the potential as a novel intervention target for aggressive HCC.

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Diverse roles of SERPINE1 in regulating cellular proliferation and invasion

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