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Oncogene. 2018 Oct;37(42):5605-5617. doi: 10.1038/s41388-018-0364-3. Epub 2018 Jun 15.

hMENA isoforms impact NSCLC patient outcome through fibronectin/β1 integrin axis.

Author information

1
Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.
2
Department of Molecular Medicine, University Sapienza, Rome, Italy.
3
Laboratory of Pathology, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.
4
Biostatistics-Scientific Direction, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.
5
Department of Physics, University Sapienza, Rome, Italy.
6
Thoracic Surgery Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.
7
Department of Pharmacology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
8
Yale Cardiovascular Research Center, Departments of Internal Medicine, Cell Biology and Biomedical Engineering, Yale School of Medicine, New Haven, CT, 06511, USA.
9
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, 94720, USA.
10
Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. paola.nistico@ifo.gov.it.

Abstract

We demonstrated previously that the splicing of the actin regulator, hMENA, generates two alternatively expressed isoforms, hMENA11a and hMENAΔv6, which have opposite functions in cell invasiveness. Their mechanisms of action have remained unclear. Here we report two major findings: (i) hMENA regulates β1 integrin expression. This was shown by depleting total hMENA, which led to loss of nuclear expression of serum response factor (SRF)-coactivator myocardin-related transcription factor 1 (MRTF-A), leading to an increase in the G-actin/F-actin ratio crucial for MRTF-A localization. This in turn inhibited SRF activity and the expression of its target gene β1 integrin. (ii) hMENA11a reduces and hMENAΔv6 increases β1 integrin activation and signaling. Moreover, exogenous expression of hMENA11a in hMENAΔv6-positive cancer cells dramatically reduces secretion of extracellular matrix (ECM) components, including β1 integrin ligands and metalloproteinases. On the other hand, overexpression of the pro-invasive hMENAΔv6 increases fibronectin production. In primary tumors high hMENA11a correlates with low stromal fibronectin and a favorable clinical outcome of early node-negative non-small-cell lung cancer patients. These data provide new insights into the roles of hMENA11a and hMENAΔv6 in the druggable β1 integrin-ECM signaling axis and allow stratification of patient risk, guiding their clinical management.

PMID:
29907768
PMCID:
PMC6193944
DOI:
10.1038/s41388-018-0364-3
[Indexed for MEDLINE]
Free PMC Article

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