Abstract
Cancer stem cells (CSCs) are believed to be the main source of cancer relapse and metastasis. PIWI-interacting small non-coding RNAs (piRNAs) have been recently recognized to be relevant to cancer biology. Whether and how piRNAs regulate human CSCs remain unknown. Herein, upregulation of piR-823 was identified in tested luminal breast cancer cells, especially in the luminal subtype of breast CSCs. Enforced expression or targeted knockdown of piR-823 demonstrated its oncogenic function in regulating cell proliferation and colony formation in MCF-7 and T-47D breast cancer cells. In addition, piR-823 induced ALDH (+) breast CSC subpopulation promoted the expression of stem cell markers including OCT4, SOX2, KLF4, NANOG, and hTERT, and increased mammosphere formation. Tail vein injection of magnetic nanoparticles carrying anti-piR-823 into the mammary gland of tumor-burdened mice significantly inhibited tumor growth in vivo. DNA methyltransferases (DNMTs) including DNMT1, DNMT3A, and DNMT3B were demonstrated to be the downstream genes of piR-823, which regulate gene expression by maintaining DNA methylation. piR-823 increased the expression of DNMTs, promoted DNA methylation of gene adenomatous polyposis coli (APC), thereby activating Wnt signaling and inducing cancer cell stemness in the luminal subtype of breast cancer cells. The current study not only revealed a novel mechanism through which piRNAs contribute to tumorigenesis in breast cancer by regulating CSCs, but also provided a therapeutic strategy using non-coding genomes in the suppression of human breast cancer.
Highlights
In the last few decades, non-coding RNAs have been demonstrated to play important roles in regulating gene expression and biological processes
In order to address this question, we isolated ALDH + breast cancer stem cells (CSCs) from MCF-7 human breast cancer cells (Figure 1A) for cancer-associated P-elementinduced wimpy testis (PIWI)-interacting small non-coding RNAs (piRNAs) screening analysis, and identified that piR-823 was significantly upregulated in the ALDH + subpopulation of MCF-7 cells (Figure 1B)
Nine pairs of clinical tissue samples of luminal breast cancer were applied for piR-823 analysis, further indicating the upregulation of piR-823 in the tumors compared to normal tissues (Figure 1D)
Summary
In the last few decades, non-coding RNAs (ncRNAs) have been demonstrated to play important roles in regulating gene expression and biological processes. Long ncRNAs (lncRNAs), circular ncRNAs (circRNAs), and small ncRNAs including microRNAs (miRNAs), P-elementinduced wimpy testis (PIWI)-interacting RNAs (piRNAs), and small interfering RNAs (siRNAs) piRNA-823 Regulates Cancer Stem Cells are involved in the regulation of cancer development and progression mostly by regulating gene expression at the transcriptional and post-transcriptional levels via RNA-RNA or RNA-DNA or RNA-protein interactions (Anastasiadou et al, 2017; Romano et al, 2017). PiRNAs are supposed to regulate tumorigenesis and tumor progression by epigenetic regulation at the genome DNA level and/or gene translation at the message RNA level, the mechanisms regulating CSCs are yet to be determined
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