TGFβ promotes breast cancer stem cell self-renewal through an ILEI/LIFR signaling axis

Autor: Toros Dincman, Breege V. Howley, Simon Grelet, Alec N. Woosley, Shaun K. Olsen, Bidyut K. Mohanty, Annamarie C. Dalton, Philip H. Howe, George S. Hussey, Sean Bloos
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Leukemia Inhibitory Factor Receptor alpha Subunit
Cell
Leukemia inhibitory factor receptor
Heterogeneous-Nuclear Ribonucleoproteins
Metastasis
tumor initiating cell
hnRNP E1
0302 clinical medicine
Mice
Inbred NOD
Transforming Growth Factor beta
Breast cancer stem cell
Cell Self Renewal
RNA-Binding Proteins
3. Good health
Neoplasm Proteins
DNA-Binding Proteins
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cytokines
Female
Signal transduction
Stem cell
Signal Transduction
STAT3 Transcription Factor
Epithelial-Mesenchymal Transition
Breast Neoplasms
Biology
Article
Fam3C
03 medical and health sciences
PCBP1
Cancer stem cell
Cell Line
Tumor
Genetics
medicine
Gene silencing
metastasis
Animals
Humans
Molecular Biology
ILEI
LIFR
Mammary Neoplasms
Experimental
Epithelial Cells
medicine.disease
030104 developmental biology
Tumor progression
Cancer research
Zdroj: Oncogene
ISSN: 1476-5594
0950-9232
Popis: FAM3C/Interleukin-like EMT Inducer (ILEI) is an oncogenic member of the FAM3 cytokine family and serves essential roles in both epithelial-mesenchymal transition (EMT) and breast cancer metastasis. ILEI expression levels are regulated through a non-canonical TGFβ signaling pathway by 3′-UTR-mediated translational silencing at the mRNA level by hnRNP E1. TGFβ stimulation or silencing of hnRNP E1 increases ILEI translation and induces an EMT program that correlates with enhanced invasion and migration. Recently, EMT has been linked to the formation of breast cancer stem cells (BCSCs) that confer both tumor cell heterogeneity as well as chemoresistant properties. Herein, we demonstrate that hnRNP E1 knockdown significantly shifts normal mammary epithelial cells to mesenchymal BCSCs in vitro and in vivo. We further validate that modulating ILEI protein levels results in the abrogation of these phenotypes, promoting further investigation into the unknown mechanism of ILEI signaling that drives tumor progression. We identify LIFR as the receptor for ILEI, which mediates signaling through STAT3 to drive both EMT and BCSC formation. Reduction of either ILEI or LIFR protein levels results in reduced tumor growth, fewer tumor initiating cells and reduced metastasis within the hnRNP E1 knock-down cell populations in vivo. These results reveal a novel ligand-receptor complex that drives the formation of BCSCs and represents a unique target for the development of metastatic breast cancer therapies.
Databáze: OpenAIRE
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