Matrix metalloproteinase 12 promotes tumor propagation in the lung.

Abstract

OBJECTIVE:

Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor-derived versus immune-derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis.

METHODS:

We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non-small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies.

RESULTS:

Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness.

CONCLUSIONS:

We suggest that tumor cell-derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.

• Authors: Ezra Ella, Yaniv Harel, Michal Abraham, Hanna Wald, Ofra Benny, Adi Karsch-Bluman, Dive Vincent, Devel Laurent, Gail Amir, Uzi Izhar, Oz M Shapira, David Yoon, Hyun-Sung Lee, David J Sugarbaker, Bryan Burt, Amnon Peled, Ori Wald
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 155 Issue 5 Pg. 2164-2175.e1 (05 2018) ISSN: 1097-685X [Electronic] United States
• PMID: 29429629 (Publication Type: Journal Article, Webcast)
• Copyright: Copyright © 2018 The American Association for Thoracic Surgery. All rights reserved.

Chemical References

• Biomarkers, Tumor
• MMP12 protein, human
• Matrix Metalloproteinase 12
• matrix metallopeptidase 12, mouse

Topics

• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Lewis Lung (enzymology, genetics, pathology)
• Carcinoma, Non-Small-Cell Lung (enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Movement
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (enzymology, genetics, pathology)
• Male
• Matrix Metalloproteinase 12 (genetics, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasm Invasiveness
• Signal Transduction