Oestrogen inhibition of apoptosis causes upregulation of KLF5 and poor prognosis in female non-small cell lung cancer patients

Abstract

Background

KLF5 is closely related to tumour growth, proliferation, and blood vessel formation. Our study was designed to explore the role of KLF5 in non-small cell lung cancer (NSCLC) and its impact on clinical prognosis.

Methods

Lung tissue specimens of patients diagnosed with NSCLC were collected, and KLF5 protein expression was detected in tissues. We then compared KLF5 expression levels in NSCLC patients of different sexes and its impact on clinical features using samples from the TCGA and GEPIA databases, and performed GO and KEGG enrichment analyses on KLF5, ESR1 and related genes. Finally, in vitro experiments using NSCLC PC-9 cells demonstrated estradiol mediated regulation of KLF5 expression and apoptosis were demonstrated at the cellular level.

Results

KLF5 mRNA was 2.5-fold higher in NSCLC tissues vs. adjacent tissues (p = 0.003), and protein levels increased by 1.8-fold (p = 0.01), which indicated that KLF5 was significantly over-expressed in cancerous tissues of NSCLC patients. This consistent over-expression pattern was clinically consequential, as survival analysis revealed the poor prognosis of patients was related to the over-expression of KLF5. Further analysis showed that KLF5 expression was lower in female patients than in male patients. Multivariate regression analysis showed that high KLF5 expression (HR = 1.328, p < 0.05) was an independent risk factor for lung cancer prognosis, but only in female patients. Oestrogen and oestrogen receptor inhibitors were shown to mediate KLF5 protein expression at the cellular level. In addition, with increasing concentrations of oestrogen, the expression of Bcl2 was progressively increased, the expression of Bax was progressively down-regulated, and the apoptosis of NSCLC cells decreases, and that this effect was dependent on the regulation of KLF5.

Conclusion

Estrogen upregulates KLF5, which suppresses pro-apoptotic Bax and enhances anti-apoptotic Bcl-2, reducing caspase-3 activation KLF5 may represent a potential therapeutic target for female NSCLC, warranting further preclinical and clinical investigation These findings are primarily derived from in vitro models; future in vivo studies are needed to confirm clinical relevance.