A Significance of MMP-1 in EGFR-TKI Resistant Lung Adenocarcinoma: A Potential of Therapeutic Target Running title: A Role of MMP-1 in EGFR-TKI Resistant Lung Adenocarcinoma Authors:
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Manuscript title A Significance of MMP-1 in EGFR-TKI Resistant Lung Adenocarcinoma: A Potential of Therapeutic Target Running title: A Role of MMP-1 in EGFR-TKI Resistant Lung Adenocarcinoma Authors: Ryoko Saito, [email protected] Yasuhiro Miki, [email protected] Naoya Ishida, [email protected] Chihiro Inoue, [email protected] Masayuki Kobayashi, [email protected] Shuko Hata, [email protected] Hisafumi Yamada-Okabe, [email protected] Yoshinori Okada, [email protected] Hironobu Sasano, [email protected] Institution: 1 Department of Pathology, Tohoku University Graduate School of Medicine, 2 Department of Pathology, Tohoku Medical and Pharmaceutical University School of Medicine, 3 CHUGAI Pharmaceutical Co., Ltd. 4 Department of Thoracic Surgery, Tohoku University Hospital Correspondence: Department of Pathology, Tohoku University School of Medicine, Ryoko Saito, Seiryo-machi 2-1, Aoba-ku, Sendai, Miyagi, Japan J 980-8575 Tel +81-22-717-8050, Fax +81-22-273-8051, [email protected] Abstract: Lung adenocarcinoma with EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance was reported to harbor higher ability of invasion and migration than those sensitive to EGFR-TKI, but the function of MMPs (matrix metalloproteinases) has not been explored in EGFR-TKI resistant lung adenocarcinoma. In this study, the correlation between immunohistochemical status of MMP-1 and clinicopathological factors were analyzed in 89 lung adenocarcinoma. We performed microarray, migration assay and invasion assay using EGFR-TKI sensitive cell lines and EGFR-TKI resistant cell lines. To clarify the mechanism of MMP-1 induction, we treated lung adenocarcinoma cells with EGF and rapamycin, performed phosphorylation antibody array and analyzed the correlation between MMP-1 expression and EGFR or mTOR (mammalian target of rapamycin) pathway. As a result, we firstly demonstrated that MMP-1 played an important role in migration and invasion abilities of EGFR-TKI resistant lung adenocarcinoma, and that mTOR pathway could be associated with an induction of MMP-1. We demonstrated the significant positive correlation between MMP-1 status in lung adenocarcinoma cells and the history of smoking, and the subtype of invasive mucinous adenocarcinoma. In conclusion, This study provides insights into the development of a possible alternative therapy manipulating MMP-1 and mTOR signaling pathway in EGFR-TKI resistant lung adenocarcinoma.
منابع مشابه
The Significance of MMP-1 in EGFR-TKI–Resistant Lung Adenocarcinoma: Potential for Therapeutic Targeting
Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance is one of the most important problems in lung cancer therapy. Lung adenocarcinoma with EGFR-TKI resistance was reported to have higher abilities of invasion and migration than cancers sensitive to EGFR-TKI, but the function of matrix metalloproteinases (MMPs) has not been explored in EGFR-TKI-resistant lung adenoca...
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