It is important to establish cancer stem cell (CSC)-targeted therapies to eradicate cancer. As it is a CSC marker, we focused on Kruppel-like factor 5 (KLF5) in this study.
We searched for candidate microRNAs (miRNAs) that inhibited KLF5 expression by in silico analyses and screened them in colon cancer cell lines.
We identified one promising miRNA, miR-4711-5p, that downregulated KLF5 expression by direct binding. This miRNA suppressed cell proliferation, migration and invasion ability, as well as stemness, including decreased stem cell marker expression, reactive oxygen species activity and sphere formation ability. MiR-4711-5p inhibited the growth of DLD-1 xenografts in nude mice with no adverse effects. We found that miR-4711-5p provoked G1 arrest, which could be attributed to direct binding of miR-4711-5p to TFDP1 (a heterodimeric partner of the E2F family). Our findings also suggested that direct binding of miR-4711-5p to MDM2 could upregulate wild-type p53, leading to strong induction of apoptosis. Finally, we found that miR-4711-5p had a potent tumour-suppressive effect compared with a putative anti-oncomiR, miR-34a, in tumour cell cultures derived from five patients with colorectal cancer.
Our data suggest that miR-4711-5p could be a promising target for CSC therapy.
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We acknowledge the core NGS facility of the Genome Information Research Centre of Osaka University for their support in IPA and data analysis.
Ethics approval and consent to participate
All animal experiments were performed in accordance with currently prescribed guidelines and followed a protocol approved by Osaka University. This study was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients, and the study was approved by the Ethics Board of Osaka University Hospital.
Consent to publish
Informed consent was obtained from all patients for publication of this article.
The expression levels of miR-4711-5p and other miRNAs referred to in this study (Supplementary Fig. S6) are available on the Tissue Atlas website (https://ccb-web.cs.uni-saarland.de/tissueatlas/). The expression levels of KLF5 referred to in this study (Supplementary Fig. S1) are available on the Human Protein Atlas website (https://www.proteinatlas.org/). All the other data of the study can be found with the corresponding author.
The authors declare no competing interests.
This work was supported by a grant from Kagoshima Shinsangyo Sousei Investment Limited Partnership (its general partner is Kagoshima Development Co., Ltd).
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Morimoto, Y., Mizushima, T., Wu, X. et al. miR-4711-5p regulates cancer stemness and cell cycle progression via KLF5, MDM2 and TFDP1 in colon cancer cells. Br J Cancer 122, 1037–1049 (2020). https://doi.org/10.1038/s41416-020-0758-1