Metastatic traits seem to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor miRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non-small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a "stemness" transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor-like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer.
|Titolo:||Regulation of lung cancer metastasis by Klf4-numb-like signaling|
|Parole Chiave:||gene expression regulation neoplastic; signal transduction; animals; base sequence; cell line tumor; cell movement; cluster analysis; disease progression; female; gene expression profiling; humans; intracellular signaling peptides and proteins; Kruppel-like transcription factors; lung neoplasms; mice; microRNAs; neoplasm metastasis; neoplastic stem cells; RNA interference; transcription genetic|
|Settore Scientifico Disciplinare:||Settore MED/21 - Chirurgia Toracica|
Settore MED/08 - Anatomia Patologica
|Data di pubblicazione:||15-apr-2013|
|Digital Object Identifier (DOI):||10.1158/0008-5472.CAN-12-4232|
|Appare nelle tipologie:||01 - Articolo su periodico|