Diverse roles of SERPINE1 in regulating cellular proliferation and invasion.

Abstract

Serine protease inhibitor clade E member 1 (SERPINE1) is involved in various biological processes, but its role in promoting or suppressing tumorigenesis remains controversial. The present study focused on the effects of SERPINE1 downregulation on cell proliferation and invasion across three types of tumors to elucidate the underlying mechanisms. Based on data from an analysis of The Cancer Genome Atlas dataset, high SERPINE1 levels in patients with breast cancer and low‑grade glioma were associated with a poor prognosis, whereas elevated SERPINE1 expression in patients with skin cutaneous melanoma associated with improved outcomes. With respect to cell proliferation phenotypes, SERPINE1 knockdown increased xenograft growth and the proliferation of melanoma C918 cells by promoting cell cycle progression through the modulation of minichromosome maintenance complex component 3 and the activity of p53/SMAD3 regulators; conversely, SERPINE1 knockdown reduced the xenograft growth and proliferation of MDA‑MB‑231 breast cancer cells by decreasing the urokinase‑type plasminogen activator receptor‑mediated ERK/p38 activity ratio and similarly decreased proliferation in H4 glioma cells through an heat shock protein 90‑alpha (HSP90α)‑mediated reduction in the ERK/p38 activity ratio. Regarding invasion and metastasis, SERPINE1 knockdown consistently reduced invasion, matrix metalloproteinase (MMP) activity, and lung metastasis in both C918 and MDA‑MB‑231 cells but paradoxically increased invasion and MMP‑1 activity in H4 cells through the HSP90α‑p38‑MMP‑1 axis. Collectively, these findings suggested that SERPINE1 exerts diverse effects on cell proliferation and invasion through multiple regulatory mechanisms. These findings indicated that therapy targeting SERPINE1, which involves a comprehensive understanding of its diverse mechanisms of function, can increase treatment precision and reduce adverse reactions.