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Cancer Res. 2016 Jan 15;76(2):197-205. doi: 10.1158/0008-5472.CAN-15-1228. Epub 2015 Nov 10.

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

Author information

1
Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
2
Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany. brigitte.puetzer@med.uni-rostock.de.

Abstract

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.

PMID:
26554827
DOI:
10.1158/0008-5472.CAN-15-1228
[Indexed for MEDLINE]
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