Identification of miR-34a as a potent inhibitor of prostate cancer progenitor cells and metastasis by directly repressing CD44

Abstract

Cancer stem cells (CSCs) or tumor progenitor cells are involved in tumor progression and metastasis 1. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs 2– 5 and miRNA dysregulation has been implicated in tumorigenesis 6. CSCs in many tumors, including cancers of the breast 7, pancreas 8, head and neck 9, colon 10, 11, small intestine 12, liver 13, stomach 14, bladder 15, and ovary 16 have been identified using adhesion molecule CD44, either individually or in combination with other marker(s). Prostate cancer (PCa) stem/progenitor cells with enhanced clonogenic 17 and tumor-initiating and metastatic 18, 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 target 20– 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.