TY - JOUR
T1 - miR-4711-5p regulates cancer stemness and cell cycle progression via KLF5, MDM2 and TFDP1 in colon cancer cells
AU - Morimoto, Yoshihiro
AU - Mizushima, Tsunekazu
AU - Wu, Xin
AU - Okuzaki, Daisuke
AU - Yokoyama, Yuhki
AU - Inoue, Akira
AU - Hata, Tsuyoshi
AU - Hirose, Haruka
AU - Qian, Yamin
AU - Wang, Jiaqi
AU - Miyoshi, Norikatsu
AU - Takahashi, Hidekazu
AU - Haraguchi, Naotsugu
AU - Matsuda, Chu
AU - Doki, Yuichiro
AU - Mori, Masaki
AU - Yamamoto, Hirofumi
N1 - Funding Information:
Funding information This work was supported by a grant from Kagoshima Shinsangyo Sousei Investment Limited Partnership (its general partner is Kagoshima Development Co., Ltd).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.
PY - 2020/3/31
Y1 - 2020/3/31
N2 - 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.
AB - 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.
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U2 - 10.1038/s41416-020-0758-1
DO - 10.1038/s41416-020-0758-1
M3 - Article
C2 - 32066912
AN - SCOPUS:85079697595
SN - 0007-0920
VL - 122
SP - 1037
EP - 1049
JO - British journal of cancer
JF - British journal of cancer
IS - 7
ER -
