p73 and IGF1R Regulate Emergence of Aggressive Cancer Stem-like Features via miR-885-5p Control

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 2; pp. 197 - 205
• Main Authors: Meier, Claudia, Hardtstock, Philip, Joost, Sophie, Alla, Vijay, Pützer, Brigitte M
• Format: Journal Article
• Language: English
• Published: United States 15.01.2016
• Subjects: Animals; Cell Line, Tumor; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; HEK293 Cells; Heterografts; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplastic Stem Cells - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Receptors, Somatomedin - metabolism; Transfection; Tumor Protein p73; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-1228

Cancer stem-like cells (CSC) have been proposed to promote cancer progression by initiating tumor growth at distant sites, suggesting that stem-like cell features can support metastatic efficiency. Here, we demonstrate that oncogenic DNp73, a dominant-negative variant of the tumor-suppressor p73, confers cancer cells with enhanced stem-like properties. DNp73 overexpression in noninvasive melanoma and lung cancer cells increased anchorage-independent growth and elevated the expression of the pluripotency factors CD133, Nanog, and Oct4. Conversely, DNp73 depletion in metastatic cells downregulated stemness genes, attenuated sphere formation and reduced the tumor-initiating capability of spheroids in tumor xenograft models. Mechanistic investigations indicated that DNp73 acted by attenuating expression of miR-885-5p, a direct regulator of the IGF1 receptor (IGF1R) responsible for stemness marker expression. Modulating this pathway was sufficient to enhance chemosensitivity, overcoming DNp73-mediated drug resistance. Clinically, we established a correlation between low p73 function and high IGF1R/CD133/Nanog/Oct4 levels in melanoma specimens that associated with reduced patient survival. Our work shows how DNp73 promotes cancer stem-like features and provides a mechanistic rationale to target the DNp73-IGF1R cascade as a therapeutic strategy to eradicate CSC.