TY - JOUR
T1 - MIR-137 regulates the tumorigenicity of colon cancer stem cells through the inhibition of DCLK1
AU - Sakaguchi, Masazumi
AU - Hisamori, Shigeo
AU - Oshima, Nobu
AU - Sato, Fumiaki
AU - Shimono, Yohei
AU - Sakai, Yoshiharu
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/4
Y1 - 2016/4
N2 - miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused onmiRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colon CSCs (EpCAM+/CD44+/CD66a-) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1 (DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive cancer cells were widely distributed in clinically resected colon cancer specimens, while DCLK1-positve epithelial cells were rarely detected in normal colon tissues including the crypt bottoms. Luciferase assay and immunoblot analysis revealed that miR-137 regulated DCLK1 gene expression. Transduction of exogenous miR-137 suppressed the development of colon cancer organoids in vitro and the tumorigenicity of colon cancer cells in vivo without affecting the growth of normal intestinal organoids. Furthermore, the suppression of miR-137 enhanced the organoid development of normal colon cells. These data demonstrate that miR-137 has the capacity to suppress the tumorigenicity of colon CSCs and that maintained expression of miR-137 in NCSCs contributes to suppressing uncontrolled cell proliferation through the inhibition of DCLK1 expression.
AB - miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused onmiRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colon CSCs (EpCAM+/CD44+/CD66a-) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1 (DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive cancer cells were widely distributed in clinically resected colon cancer specimens, while DCLK1-positve epithelial cells were rarely detected in normal colon tissues including the crypt bottoms. Luciferase assay and immunoblot analysis revealed that miR-137 regulated DCLK1 gene expression. Transduction of exogenous miR-137 suppressed the development of colon cancer organoids in vitro and the tumorigenicity of colon cancer cells in vivo without affecting the growth of normal intestinal organoids. Furthermore, the suppression of miR-137 enhanced the organoid development of normal colon cells. These data demonstrate that miR-137 has the capacity to suppress the tumorigenicity of colon CSCs and that maintained expression of miR-137 in NCSCs contributes to suppressing uncontrolled cell proliferation through the inhibition of DCLK1 expression.
UR - http://www.scopus.com/inward/record.url?scp=84963815375&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84963815375&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-15-0380
DO - 10.1158/1541-7786.MCR-15-0380
M3 - Article
C2 - 26747706
AN - SCOPUS:84963815375
SN - 1541-7786
VL - 14
SP - 354
EP - 362
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 4
ER -