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

By Can Liu, Kevin Kelnar, Bigang Liu, Xin Chen, Tammy Calhoun‐Davis, Hangwen Li, Lubna Patrawala, Hong Yan, Collene R. Jeter, S. Honorio and 5 more. Nature Medicine, 2011

1,193 citations recorded by the source corpus.

Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors—including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary—have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic 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 target, 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.

Subfields: Cancer Research, Oncology

View Paper: https://www.semanticscholar.org/paper/3f0acdb37da409be1682767f121d3d98d8fd93d9

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In Cancer Research

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Citations in the corpus

• miR-34 – a microRNA replacement therapy is headed to the clinic (2012, methodology): “Overexpression of miR-34a, either by transient transfection or stable genomic integration via a retrovirus, interferes with sphere formation in soft agar and tumorigenicity in vivo (Liu et al., 2011).”
• Cancer stem cells: current status and evolving complexities. (2012, background): “Notably, systemic delivery of miR-34a, which is expressed at low levels in prostate CSCs, inhibited metastasis of prostate cancer cells and prolonged survival of mice (Liu et al., 2011).”
• The biology and role of CD44 in cancer progression: therapeutic implications (2018, background): “Knock-down of CD44 photocopied miR-34a overexpression by inhibiting prostate cancer regeneration and metastasis [113].”
• MicroRNA and cancer (2012, positive): “Corroborating these findings, reintroduction of lipid-formulated miR-34 in both a spontaneous lung cancermodel and in a xenograftmodel using pancreatic cancer cells resulted in reduced tumour growth (Liu et al., 2011; Trang et al., 2011).”