A study on simvastatin inhibiting pancreatic neuroendocrine tumor cell proliferation via regulation of the KLF4-mediated MAPK/ERK pathway
SHI Xiaoting
ZHOU Lu
YE Mujie
YAN Lijun
TANG Qiyun
Abstract：Objective To investigate the anti-tumor mechanism of simvastatin in pancreatic neuroendocrine neoplasms(pNENs)through regulating Krüppel-like factor 4(KLF4)and subsequently suppressing the mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK)signaling pathway.Methods Differentially expressed genes after simvastatin treatment were screened by RNA sequencing.The expression pattern of KLF4 in various cancers and its correlation with patient prognosis were analyzed using the TIMER2.0 and GEPIA2 databases.Reverse transcription-quantitative PCR(RT-qPCR)and Western blot were performed to validate the effect of simvastatin on KLF4 expression at transcriptional and protein levels.In QGP-1 cells with low endogenous KLF4 expression,a KLF4-overexpressing plasmid was constructed.Cell proliferation was assessed by CCK-8 assay,EdU incorporation assay,and colony formation assay.Western blot was further used to examine changes in key proteins of the MAPK/ERK pathway.Results RNA-seq results showed that KLF4 expression was upregulated after simvastatin treatment.Bioinformatics analyses indicated that KLF4 was lowly expressed in multiple tumor tissues,and its high expression was positively correlated with favorable prognosis in several cancers(P＜0.05).Both RT-qPCR and Western blot confirmed that simvastatin treatment significantly increased KLF4 expression at mRNA and protein levels(P＜0.05).Successful overexpression of KLF4 in stable transfection cells was verified by Western blot(P＜0.001).CCK-8,colony formation,and EdU assays consistently demonstrated that KLF4 overexpression significantly suppressed the proliferation of QGP-1 cells.Furthermore,Western blot analysis revealed that KLF4 overexpression markedly reduced phosphorylated ERK(pERK)levels(P＜0.001).Conclusion Simvastatin exerts anti-tumor effects in pNENs by upregulating KLF4 expression and inhibiting the MAPK/ERK signaling pathway.
Keywords：pancreatic neuroendocrine tumorsimvastatinkrüppel-like factor 4mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway
Publication Date：2026-02-28
Online Publishing Date：2026-04-01(First online date of this platform, not the publication date of the document)
Pages：7( 134-140 )