A positive feedback loop between KPNA2 and FOXM1 promotes the proliferation of lung adenocarcinoma

TL;DR

This study identifies a feedback loop between KPNA2 and FOXM1 that promotes lung adenocarcinoma cell growth, suggesting new therapeutic targets.

Contribution

The discovery of a positive feedback loop between KPNA2 and FOXM1 in lung adenocarcinoma.

Findings

KPNA2 is upregulated in lung adenocarcinoma and its inhibition reduces cancer cell proliferation.

FOXM1 directly controls KPNA2 expression, and KPNA2 suppression lowers FOXM1 levels.

A positive feedback loop between KPNA2 and FOXM1 enhances lung adenocarcinoma cell proliferation.

Abstract

Lung adenocarcinoma is a prevalent form of non-small cell lung cancer (NSCLC) that accounts for approximately 40% of all lung cancers. However, despite significant therapeutic advances in recent years, the overall survival of patients with lung adenocarcinoma remains poor. Consequently, it is necessary to identify further novel targets and drugs that can contribute to enhancing the prognosis of these patients. To this end, in this study, using siRNA silencing, we initially knocked down KPNA2 in lung adenocarcinoma cell lines, and performed CCK8 and 5-ethynyl-2ʹ-deoxyuridine assays to examine the proliferation of lung adenocarcinoma. Chromatin immunoprecipitation was used to determine whether the transcription factor FOXM1 can bind to the promoter region of KPNA2, and we used AlphaFold3 to predict the proteins that bind to KPNA2 and to characterize the binding sites on these proteins. We found that KPNA2 is upregulated in lung adenocarcinoma and that inhibiting its expression effectively reduced the proliferation of lung adenocarcinoma cancer cells. Both bioinformatics analyses and experimental findings provided evidence that the expression of KPNA2 is directly controlled by FOXM1. Furthermore, we observed a reduction in FOXM1 expression following the suppression of KPNA2. These findings indicate the presence of a positive feedback loop between the expression of KPNA2 and FOXM1, which contributes to an enhanced proliferation of lung adenocarcinoma cells.

The online version contains supplementary material available at 10.1186/s40001-025-03674-1.

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