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

Abstract

The authors show that miR-34a regulates progenitor and metastatic properties of prostate cancer cells, and they identify CD44 as a relevant target of the microRNA. The inhibition of metastasis observed after systemic delivery of miR-34a suggests that it could be used as a potential therapeutic agent in prostate cancer. Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis1. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs2,3,4,5, and dysregulation of miRNAs 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 the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic17 and tumor-initiating and metastatic18,19 capacities are enriched in the CD44+ cell population, but whether miRNAs regulate CD44+ prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target20,21,22,23,24, was underexpressed in CD44+ prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44+ prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44− prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44+ prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.