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KLF4 Induces Colorectal Cancer by Promoting EMT via STAT3 Activation

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Abstract

Objective

Krüppel-like factor 4 (KLF4) has been demonstrated to exert a pro-carcinogenic effect in solid tissues. However, the precise biological function and underlying mechanisms in colorectal cancer (CRC) remains elucidated.

Aims

To investigate whether KLF4 participates in the proliferation and invasion of CRC.

Methods

The expression of KLF4 was investigated using immunohistochemistry and immunoblotting. The clinical significance of KLF4 was evaluated. Furthermore, the effect of inhibiting or overexpressing KLF4 on tumor was examined. Immunoblotting and qPCR were used to detect Epithelial–mesenchymal transition-related proteins levels. Additionally, the molecular function of KLF4 is related to the STAT3 signaling pathway and was determined through JASPAR, GSEA analysis, and in vitro experiments.

Results

KLF4 exhibits down-regulated expression in CRC and is part of the vessel invasion, TNM stage, and worse prognosis. In vitro studies have shown that KLF4 promotes cellular proliferation and invasion, as well as EMT processes. Xenograft tumor models confirmed the oncogenic role of KLF4 in nude mice. Furthermore, GSEA and JASPAR databases analysis reveal that the binding of KLF4 to the signal transducer and activator of transcription 3 (STAT3) promoter site induces activation of p-STAT3 signaling. Subsequent targeting of STAT3 confirmed its pivotal role in mediating the oncogenic effects exerted by KLF4.

Conclusion

The study suggests that KLF4 activates STAT3 signaling, inducing epithelial–mesenchymal transition, thereby promoting CRC progression.

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Data availability

The information examined in this study is obtainable in the TCGA (https://portal.gdc.cancer.gov/), GSEA (https://www.gsea-msigdb.org/gsea/index.jsp), and JASPAR (https://jaspar.genereg.net/) databases.

Abbreviations

KLF4:

Kruppel-like factor 4

STAT3:

Signal transducer and activator of transcription 3

p-STAT3:

Phosphorylation of STAT3

CRC:

Colorectal cancer

EMT:

Epithelial–mesenchymal transition

TCGA:

The Cancer Genome Atlas

CHIP:

Chromatin immunoprecipitation

IHC:

Immunohistochemistry

GSEA:

Gene set enrichment analysis

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Acknowledgment

Thanks to my colleagues for their contributions.

Funding

This work was funded by Science and Technology Project of Jiangxi Province (GJJ2200241).

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Author notes

  1. Lebin Yuan and Yanqiu Meng have contributed equally to this work.

Authors and Affiliations

  1. Molecular Centre Laboratory, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

    Jiajia **ang

  2. Department of Nail and Breast Surgery, Affiliated **angyang Central Hospital of Hubei University of Arts and Science, **angyang Center Hospital, **angyang, Hubei, China

    Lebin Yuan

  3. Oncology Department, First Affiliated Hospital of Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

    Yanqiu Meng

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  1. Lebin Yuan
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Contributions

L.Y. and Y.M. carried out the formal analysis and drafted the initial manuscript; J.X. oversaw the project administration; L.Y. conducted the experiments. Y.M. participated in software analysis; L.Y. and J.X. conducted data curation; L.Y., Y.M., and J.X. were instrumental in authoring, critically revising, and editing the manuscript; all contributors thoroughly reviewed and endorsed the final version submitted for publication.

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Correspondence to Jiajia **ang.

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In compliance with local laws and institutional guidelines, ethical review and approval were waived for this research involving human participants. Similarly, in adherence to national regulations and institutional standards, written informed consent from participants was not necessary for this study.

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Yuan, L., Meng, Y. & **ang, J. KLF4 Induces Colorectal Cancer by Promoting EMT via STAT3 Activation. Dig Dis Sci (2024). https://doi.org/10.1007/s10620-024-08473-y

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