Maintenance of the stemness in CD44(+) HCT-15 and HCT-116 human colon cancer cells requires miR-203 suppression.

Abstract:

:The purpose of this study was to isolate cancer stem cells (CSCs, also called tumor-initiating cells, TICs) from established human colorectal carcinoma (CRC) cell lines, characterize them extensively and dissect the mechanism for their stemness. Freshly isolated CD44(+) and CD44(-) cells from the HCT-15 human colon cancer cell line were subjected to various analyses. Interestingly, CD44(+) cells exhibited higher soft agar colony-forming ability and in vivo tumorigenicity than CD44(-) cells. In addition, the significant upregulation of the protein Snail and the downregulation of miR-203, a stemness inhibitor, in CD44(+) cells suggested that this population possessed higher invasion/metastasis and differentiation potential than CD44(-) cells. By manipulating the expression of CD44 in HCT-15 and HCT-116 cells, we found that the levels of several EMT activators and miR-203 were positively and negatively correlated with those of CD44, respectively. Further analyses revealed that miR-203 levels were repressed by Snail, which was shown to bind to specific E-box(es) present in the miR-203 promoter. In agreement, silencing miR-203 expression in wild-type HCT-116 human colon cancer cells also resulted in an increase of their stemness. Finally, we discovered that c-Src kinase activity was required for the downregulation of miR-203 in HCT-15 cells, which was stimulated by the interaction between hyaluronan (HA) and CD44. Taken together, CD44 is a critical molecule for modulating stemness in CSCs. More importantly, we show for the first time that the downregulation of miR-203 by HA/CD44 signaling is the main reason for stemness-maintenance in colon cancer cells.

journal_name

Stem Cell Res

journal_title

Stem cell research

authors

Ju SY,Chiou SH,Su Y

doi

10.1016/j.scr.2013.09.011

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

86-100

issue

1

eissn

1873-5061

issn

1876-7753

pii

S1873-5061(13)00137-2

journal_volume

12

pub_type

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