Ezra Ella1, Yaniv Harel1, Michal Abraham1, Hanna Wald1, Ofra Benny2, Adi Karsch-Bluman2, Dive Vincent3, Devel Laurent3, Gail Amir4, Uzi Izhar5, Oz M Shapira5, David Yoon6, Hyun-Sung Lee6, David J Sugarbaker6, Bryan Burt6, Amnon Peled1, Ori Wald7. 1. Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel. 2. School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel. 3. CEA Saclay, SIMOPRO, Gif/Yvette, France. 4. Department of Pathology, Hadassah University Hospital, Jerusalem, Israel. 5. Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel. 6. Division of General Thoracic Surgery, Michael E. DeBakey Department of General Surgery, Baylor College of Medicine, Houston, Tex. 7. Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel; Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel. Electronic address: ori.wald@mail.huji.ac.il.
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.
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 humanlung 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 malignanciesmatrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.
Authors: Thai-Vu T Ton; Ramesh C Kovi; Teja N Peddada; Raveena M Chhabria; Keith R Shockley; Norris D Flagler; Kevin E Gerrish; Ronald A Herbert; Mamta Behl; Mark J Hoenerhoff; Robert C Sills; Arun R Pandiri Journal: Arch Toxicol Date: 2021-09-01 Impact factor: 6.168
Authors: Alexandra Noël; Zakia Perveen; Rui Xiao; Harriet Hammond; Viviana Le Donne; Kelsey Legendre; Manas Ranjan Gartia; Sushant Sahu; Daniel B Paulsen; Arthur L Penn Journal: Front Physiol Date: 2021-11-29 Impact factor: 4.566