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Int. J. Mol. Sci. 2018, 19(2), 609; https://doi.org/10.3390/ijms19020609

The Significance of MMP-1 in EGFR-TKI–Resistant Lung Adenocarcinoma: Potential for Therapeutic Targeting

1
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
2
Department of Pathology, Tohoku Medical and Pharmaceutical University School of Medicine, Sendai 981-8558, Japan
3
CHUGAI Pharmaceutical Co., Ltd., Gotemba 412-8513, Japan
4
Department of Thoracic Surgery, Tohoku University Hospital, Sendai 980-8574, Japan
*
Author to whom correspondence should be addressed.
Received: 16 January 2018 / Revised: 14 February 2018 / Accepted: 16 February 2018 / Published: 18 February 2018
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

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 adenocarcinoma. This study aims to clarify the significance of MMP-1 in EGFR-TKI–resistant lung adenocarcinoma. From the results of in vitro studies of migration and invasion assays using EGFR-TKI–sensitive and –resistant cell lines and phosphorylation antibody arrays using EGF and rapamycin, we first demonstrate that overexpression of MMP-1, which might follow activation of a mammalian target of rapamycin (mTOR) pathway, plays an important role in the migration and invasion abilities of EGFR-TKI–resistant lung adenocarcinoma. Additionally, immunohistochemical studies using 89 cases of lung adenocarcinoma demonstrate that high expression of MMP-1 is significantly correlated with poor prognosis and factors such as smoking history and the subtype of invasive mucinous adenocarcinoma. These are consistent with the results of this in vitro study. To conclude, this study provides insights into the development of a possible alternative therapy manipulating MMP-1 and the mTOR signaling pathway in EGFR-TKI–resistant lung adenocarcinoma. View Full-Text
Keywords: MMP-1; EGFR-TKI resistance; lung adenocarcinoma; mTOR MMP-1; EGFR-TKI resistance; lung adenocarcinoma; mTOR
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Saito, R.; Miki, Y.; Ishida, N.; Inoue, C.; Kobayashi, M.; Hata, S.; Yamada-Okabe, H.; Okada, Y.; Sasano, H. The Significance of MMP-1 in EGFR-TKI–Resistant Lung Adenocarcinoma: Potential for Therapeutic Targeting. Int. J. Mol. Sci. 2018, 19, 609.

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