miR‐10b expression in breast cancer stem cells supports self‐renewal through negative PTEN regulation and sustained AKT activation

Abstract

Cancer stem cells (CSCs) are linked to metastasis. Moreover, a discrete group of miRNAs (metastamiRs) has been shown to promote metastasis. Accordingly, we propose that miRNAs that function as metastatic promoters may influence the CSC phenotype. To study this issue, we compared the expression of 353 miRNAs in CSCs enriched from breast cancer cell lines using qRT-PCR analysis. One of the most altered miRNAs was miR-10b, which is a reported promoter of metastasis and migration. Stable overexpression of miR-10b in MCF-7 cells (miR-10b-OE cells) promoted higher self-renewal and expression of stemness and epithelialmesenchymal transition (EMT) markers. In agreement with these results, inhibiting miR-10b expression using synthetic antisense RNAs resulted in a decrease in CSCs self-renewal. Bioinformatics analyses identified several potential miR-10b mRNA targets, including phosphatase and tensin homolog (PTEN), a key regulator of the PI3K/AKT pathway involved in metastasis, cell survival, and self-renewal. The targeting of PTEN by miR-10b was confirmed using a luciferase reporter, qRT-PCR, and Western blot analyses. Lower PTEN levels were observed in CSCs, and miR-10b depletion not only increased PTEN mRNA and protein expression but also decreased the activity of AKT, a downstream PTEN target kinase. Correspondingly, PTEN knockdown increased stem cell markers, whereas AKT inhibitors compromised the self-renewal ability of CSCs and breast cancer cell lines overexpressing miR-10b. In conclusion, miR-10b regulates the self-renewal of the breast CSC phenotype by inhibiting PTEN and maintaining AKT pathway activation.

MicroRNAs regulate the epithelial–mesenchymal transition and influence breast cancer invasion and metastasis

“…Overexpression of miR-10b in breast cancer cells can inhibit the expression 25 Huang et al, 32 Bahena-Ocampo et al, 33 Liang et al, 34 Ma et al, 35 Petrovic, 36 Yan et al 37 51 Rasheed et al, 52 Tavazoie et al, 53 Chou et al, 54 Zhang et al 55 43 A study showed that the upregulation of miR-155 can facilitate tumor angiogenesis, while it is associated with a poor prognosis for triple-negative breast cancer patients. 44 Kong et al 45 reported that miR-155 can act on TGF-β/Smad4 signaling through RhoA, thereby promoting the EMT; in contrast, knockdown of miR-155 can significantly inhibit the TGF-β/Smad4-induced EMT.…”

Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

“…STAT3 and KLFs can be regulated by miR-185, miR-19b, let-7, miR-22, miR-203, miR-93, miR-10b, miR-337, miR-145, and so on [99–103], and some of these microRNAs are dysregulated after SCI (Table 1). In contrast, KLF4 can directly upregulate miR-203 to promote cell senescence [104].…”

The PLGF/c‐MYC/miR‐19a axis promotes metastasis and stemness in gallbladder cancer

“…MicroRNA‐19a, by binding to the 3ʹ‐UTR, regulates multiple target genes, including PTEN , which is associated with EMT and CSC formation . Thus, we detected PTEN protein levels after treatment with the miR‐19a mimic or inhibitor (Figure H).…”