miR-4711-5p regulates cancer stemness and cell cycle progression via KLF5, MDM2 and TFDP1 in colon cancer cells
miR-4711-5p regulates cancer stemness and cell cycle progression via KLF5, MDM2 and TFDP1 in colon cancer cells
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DOI：
10.1038/s41416-020-0758-1
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发表时间：
2020-02-18
影响因子：
8.8
通讯作者：
Yamamoto, Hirofumi
中科院分区：
文献类型：
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作者：
Morimoto, Yoshihiro;Mizushima, Tsunekazu;Yamamoto, Hirofumi
研究背景建立肿瘤干细胞靶向治疗方法对根除肿瘤具有重要意义。由于它是CSC标志物，我们在本研究中集中于Kruppel样因子5（KLF 5）。方法通过计算机模拟分析寻找抑制KLF 5表达的候选microRNA（miRNAs），并在结肠癌细胞系中筛选。结果我们鉴定了一种有希望的miRNA，miR-4711- 5 p，它通过直接结合下调KLF 5的表达。该miRNA抑制细胞增殖、迁移和侵袭能力，以及干细胞性，包括降低干细胞标志物表达、活性氧活性和球体形成能力。MiR-4711- 5 p抑制裸鼠中DLD-1异种移植物的生长，没有不良反应。我们发现miR-4711- 5 p引起G1期阻滞，这可能归因于miR-4711- 5 p与TFDP 1（E2 F家族的异二聚体伴侣）的直接结合。我们的研究结果还表明，miR-4711- 5 p与MDM 2的直接结合可以上调野生型p53，导致强烈的细胞凋亡诱导。最后，我们发现miR-4711- 5 p在来自5名结直肠癌患者的肿瘤细胞培养物中具有有效的肿瘤抑制作用，与推定的抗肿瘤iR miR-34 a相比。结论miR-4711- 5 p有望成为CSC治疗的新靶点。
Background 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. Methods We searched for candidate microRNAs (miRNAs) that inhibited KLF5 expression by in silico analyses and screened them in colon cancer cell lines. Results 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. Conclusions Our data suggest that miR-4711-5p could be a promising target for CSC therapy.