The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44

Abstract

Cancer stem cells (CSCs) or tumor progenitor cells are involved in tumor progression and metastasis1. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs2–5 and miRNA dysregulation has been implicated in tumorigenesis6. CSCs in many tumors, including cancers of the breast7, pancreas8, head and neck9, colon10,11, small intestine12, liver13, stomach14, bladder15, and ovary16 have been identified using adhesion molecule CD44, either individually or in combination with other marker(s). Prostate cancer (PCa) stem/progenitor cells with enhanced clonogenic17 and tumor-initiating and metastatic18,19 capacities are also enriched in the CD44+ cell population, but whether miRNAs regulate the CD44+ PCa cells and PCa metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target20–24, was under-expressed in CD44+ PCa cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk PCa cells inhibited clonogenic expansion and tumor development. miR-34a re-expression in CD44+ PCa cells blocked whereas miR-34a antagomirs in CD44− PCa cells promoted tumor regeneration and metastasis. Systemically delivered miR-34a inhibited PCa metastasis and extended animal survival. Of significance, CD44 was identified and validated as a direct and functional target of miR-34a and CD44 knockdown phenocopied miR-34a over-expression in inhibiting PCa regeneration and metastasis. Our study reveals miR-34a as a critical negative regulator of CD44+ PCa cells and establishes a strong rationale for developing miR-34a as a novel therapeutic against prostate CSCs.

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…In fact, aberrant expression of miRNAs such as let-7, miR-34a, miR-181a, miRNA-130b in TICs has been found in a variety of tumour types. These aberrantly expressed miRNAs play essential roles in the regulation of TIC properties as either TIC suppressors or promoters [20][21][22][23][24] . Moreover, a series of critical signalling pathways involved in the regulation of TIC properties have been uncovered with the identification of the targets of these miRNAs 19,[25][26][27][28] .…”

“…Moreover, a series of critical signalling pathways involved in the regulation of TIC properties have been uncovered with the identification of the targets of these miRNAs 19,[25][26][27][28] . Importantly, miRNAs are also demonstrated to be promising biomarkers and amenable therapeutic targets 5,19,24 .…”

MicroRNA-409 suppresses tumour cell invasion and metastasis by directly targeting radixin in gastric cancers

“…Therefore, developing an effective intervention targeting metastatic disease should improve the mortality of cancer patients. Mounting evidence suggests an important role for miRNAs in the regulation of cancer metastasis, including miR-31, 20 miR-151, 26 miR-34a, 27 miR-146a 17 and miR-92a. 28 However, the functional role of miRNAs in GC metastasis is still largely unknown.…”

The emerging role of p53 in stem cells

“…Recently, p53 has been shown to regulate microRNA (miRNA) processing and also serves as an inducer of miRNA expression [7,8]; as downregulation of miRNAs is often observed in human cancer, this is an important finding that highlights the possibility of novel therapeutic approaches based on modulating the converging p53 and miRNA pathways. Among these p53-regulated miRNAs, the miR-34 family appears to be strongly involved in the control of quiescence, apoptosis and even stemness in various contexts [9]. Notably, loss of p53 correlates with decreased levels of a component of the miR-200c family and increased expression of epithelial-mesenchymal transition (EMT) factors, which have been linked to the stem cell (SC) phenotype [10].…”