KLF2 is a clinical diagnostic and treatment biomarker of breast cancer

Li, Ya-Zhao; Xie, Juan; Wang, Ruiqi; Gao, Xiaoqian; Liu, Peijun; Liu, Jie

doi:10.3389/fcell.2023.1182123

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…The infiltration scores of different cells in tumor microenvironment were evaluated by seven algorithms, including ESTIMATE ( Yoshihara et al, 2013 ), TIMER ( Li et al, 2020 ), MCP-counter ( Becht et al, 2016 ), CIBERSORT( Newman et al, 2015 ), quanTIseq ( Finotello et al, 2019 ), xCell ( Aran et al, 2017 ), and EPIC( Racle et al, 2017 ), using R package “IOBR” (version 0.99.9) ( Zeng et al, 2021 ). The correlation between the expression of SERPINE1 and marker genes of immune cells, which was obtained from a previous study, was assessed using the “Gene_Corr” module of TIMER2.0 tool ( Li et al, 2020 ; Li et al, 2023 ). The activity scores of each step of cancer-immunity cycle, which reflects the stepwise events of immune systems’ response to cancer ( Chen and Mellman, 2013 ), were calculated by Tracking Tumor Immunophenotype (TIP, http://biocc.hrbmu.edu.cn/TIP/ ) ( Xu et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Identification and validation of SERPINE1 as a prognostic and immunological biomarker in pan-cancer and in ccRCC

Li,

et al. 2023

Front. Pharmacol.

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Background:SERPINE1, a serine protease inhibitor involved in the regulation of the plasminogen activation system, was recently identified as a cancer-related gene. However, its clinical significance and potential mechanisms in pan-cancer remain obscure.Methods: In pan-cancer multi-omics data from public datasets, including The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), and online web tools were used to analyze the expression of SERPINE1 in different cancers and its correlation with prognosis, genetic alteration, DNA promoter methylation, biological processes, immunoregulator expression levels, immune cell infiltration into tumor, tumor mutation burden (TMB), microsatellite instability (MSI), immunotherapy response and drug sensitivity. Further, two single-cell databases, Tumor Immune Single-cell Hub 2 (TISCH2) and CancerSEA, were used to explore the expression and potential roles of SERPINE1 at a single-cell level. The aberrant expression of SERPINE1 was further verified in clear cell renal cell carcinoma (ccRCC) through qRT-PCR of clinical patient samples, validation in independent cohorts using The Gene Expression Omnibus (GEO) database, and proteomic validation using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database.Results: The expression of SERPINE1 was dysregulated in cancers and enriched in endothelial cells and fibroblasts. Copy number amplification and low DNA promoter methylation could be partly responsible for high SERPINE1 expression. High SERPINE1 expression was associated with poor prognosis in 21 cancers. The results of gene set enrichment analysis (GSEA) indicated SERPINE1 involvement in the immune response and tumor malignancy. SERPINE1 expression was also associated with the expression of several immunoregulators and immune cell infiltration and could play an immunosuppression role. Besides, SERPINE1 was found to be related with TMB, MSI, immunotherapy response and sensitivity to several drugs in cancers. Finally, the high expression of SERPINE1 in ccRCC was verified using qRT-PCR performed on patient samples, six independent GEO cohorts, and proteomic data from the CPTAC database.Conclusion: The findings of the present study revealed that SERPINE1 exhibits aberrant expression in various types of cancers and is associated with cancer immunity and tumor malignancy, providing novel insights for individualized cancer treatment.

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Section: Methodsmentioning

confidence: 99%

Identification and validation of SERPINE1 as a prognostic and immunological biomarker in pan-cancer and in ccRCC

Li,

et al. 2023

Front. Pharmacol.

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“…Its expression is up-regulated in rules that identify active smokers and down-regulated in those distinguishing former smokers. KLF2, commonly known as Krüppel-like factor 2, is integral to various processes, including angiogenesis, regulation of blood vessel tone, ifnflammatory responses, and lymphocyte development and migration [90]. Cigarette smoke, given its essential role in endothelial function and its anti-inflammatory and vasoprotective properties [91], impairs endothelial function, affecting the inner lining of blood vessels vital for vascular health [92].…”

Section: Qualitative Rule Parameters In Lung Endothelial Cellsmentioning

confidence: 99%

Machine Learning Reveals Impacts of Smoking on Gene Profiles of Different Cell Types in Lung

Ma,

Shen,

Guo

et al. 2024

Life

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Smoking significantly elevates the risk of lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. This risk is attributed to the harmful chemicals in tobacco smoke that damage lung tissue and impair lung function. Current research on the impact of smoking on gene expression in specific lung cells is limited. This study addresses this gap by analyzing gene expression profiles at the single-cell level from 43,539 lung endothelial cells, 234,349 lung epithelial cells, 189,843 lung immune cells, and 16,031 lung stromal cells using advanced machine learning techniques. The data, categorized by different lung cell types, were classified into three smoking states: active smoker, former smoker, and never smoker. Each cell sample encompassed 28,024 feature genes. Employing an incremental feature selection method within a computational framework, several specific genes have been identified as potential markers of smoking status in different lung cell types. These include B2M, EEF1A1, and TPT1 in lung endothelial cells; FTL and MT-ATP8 in lung epithelial cells; HLA-B and HLA-C in lung immune cells; and HSP90B1 and LCN2 in lung stroma cells. Additionally, this study developed quantitative rules for representing the gene expression patterns related to smoking. This research highlights the potential of machine learning in oncology, enhancing our molecular understanding of smoking’s harm and laying the groundwork for future mechanism-based studies.

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“…A member of the Kruppel-like factor family member, KLF2 (molecular mass = 37 kDa) controls transcription via binding to DNA with its conserved zinc-finger domains 22 . KLF2 exhibits tumor-suppressing effects in various malignancies, including breast cancer 23 , non-small cell lung cancer 24 and pancreatic cancer 25 . In breast cancer, KLF2 is a diagnostic/prognostic biomarker because it is downregulated in tumor tissues compared with para-carcinoma controls.…”

Section: Introductionmentioning

confidence: 99%

“…In breast cancer, KLF2 is a diagnostic/prognostic biomarker because it is downregulated in tumor tissues compared with para-carcinoma controls. Mechanistically, KLF2 activates dendritic cells to modulate the immune microenvironment of breast cancer and restrains angiogenesis via downregulating VEGFA and HIF1α expression 23 . In lung carcinoma, KLF2 inhibits metastasis by regulating occludin expression and the VEGF/MMP pathway, limiting vascular permeability and angiogenesis 24 .…”

Section: Introductionmentioning

confidence: 99%

MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis

Zhang,

Yu,

Bai

et al. 2024

J. Cancer

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Bicalutamide (BIC) resistance impedes the treatment of prostate cancer (PCa) and seems to involve ferroptosis; however, the underlying mechanism remains unclear. Our study aimed to explore how miR-15b-3p modulates ferroptosis in response to BIC resistance and determine whether the miRNA is suitable for early screening of PCa. Here, we found that PCa tissues had significantly higher miR-15b-3p expression than adjacent normal tissues. Analysis of blood samples in patients who underwent prostate-specific antigen (PSA) screening revealed that miR-15b-3p was a more accurate diagnostic than PSA (miR-15b-3p area under the curve [AUC] = 0.941, PSA AUC = 0.815). In vitro experiments then demonstrated that miR-15b-3p expression was markedly higher in LNCaP, PC-3, and DU145 cells than in RWPE-1 cells. Treatment with BIC decreased miR-15b-3p expression and progressive ferroptosis. Mechanistically, we identified KLF2 as the downstream target of miR-15b-3p. Overexpressing KLF2 facilitated ferroptosis via augmenting MDA and iron concentrations, in turn inhibiting the SLC7A11/GPX4 axis and decreasing GSH concentration. Through modulating ferroptosis, miR-15b-3p mimic and inhibitor weakened and enhanced BIC sensitivity, respectively. Furthermore, BIC treatment limited xenograft tumor volume in vivo, whereas agomir-15b-3p promoted tumor growth, indicating that miR-15b-3p attenuated the tumor-suppressive effects of BIC. Taken together, our results suggested that miR-15b-3p is crucial to BIC resistance, specifically via targeting KLF2 and thereby suppressing ferroptosis. High miR-15b-3p expression in early PCa screening should reflect a higher probability of cancer. In conclusion, miR-15b-3p has strong potential as a screening and diagnostic biomarker with reliable prospects for clinical application. Furthermore, because patients with high miR-15b-3p and low KLF2 expression have a greater risk of BIC resistance and malignant progression, targeting the miRNA and its downstream protein may be a new treatment strategy.

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KLF2 is a clinical diagnostic and treatment biomarker of breast cancer

Cited by 5 publications

References 46 publications

Identification and validation of SERPINE1 as a prognostic and immunological biomarker in pan-cancer and in ccRCC

Identification and validation of SERPINE1 as a prognostic and immunological biomarker in pan-cancer and in ccRCC

Machine Learning Reveals Impacts of Smoking on Gene Profiles of Different Cell Types in Lung

MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis

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