Activin upregulation by NF-κB is required to maintain mesenchymal features of cancer stem-like cells in non-small cell lung cancer

Soluble growth factors and cytokines within the tumor microenvironment aid in the induction of the epithelial-to-mesenchymal transition (EMT). Although EMT promotes the development of cancer-initiating cells (CIC), cellular mechanisms by which cancer cells maintain mesenchymal phenotypes remain poor...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Vol. 75; no. 2; p. 426
Main Authors: Wamsley, J Jacob, Kumar, Manish, Allison, David F, Clift, Sheena H, Holzknecht, Caitlyn M, Szymura, Szymon J, Hoang, Stephen A, Xu, Xiaojiang, Moskaluk, Christopher A, Jones, David R, Bekiranov, Stefan, Mayo, Marty W
Format: Journal Article
Language:English
Published: United States 15.01.2015
Subjects:
Activins - metabolism
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Epithelial-Mesenchymal Transition
Humans
Inhibin-beta Subunits - metabolism
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Mesoderm - metabolism
Mesoderm - pathology
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
NF-kappa B - metabolism
RNA, Neoplasm - biosynthesis
RNA, Neoplasm - genetics
Spheroids, Cellular
Up-Regulation
ISSN:1538-7445, 1538-7445
Online Access:Get more information
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Summary:Soluble growth factors and cytokines within the tumor microenvironment aid in the induction of the epithelial-to-mesenchymal transition (EMT). Although EMT promotes the development of cancer-initiating cells (CIC), cellular mechanisms by which cancer cells maintain mesenchymal phenotypes remain poorly understood. Work presented here indicates that induction of EMT stimulates non-small cell lung cancer (NSCLC) to secrete soluble factors that function in an autocrine fashion. Using gene expression profiling of all annotated and predicted secreted gene products, we find that NF-κB activity is required to upregulate INHBA/Activin, a morphogen in the TGFβ superfamily. INHBA is capable of inducing and maintaining mesenchymal phenotypes, including the expression of EMT master-switch regulators and self-renewal factors that sustain CIC phenotypes and promote lung metastasis. Our work demonstrates that INHBA mRNA and protein expression are commonly elevated in primary human NSCLC and provide evidence that INHBA is a critical autocrine factor that maintains mesenchymal properties of CICs to promote metastasis in NSCLC.
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ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-13-2702