Department of Pathology, Tohoku University Graduate School of Medicine, 980-8575, Sendai, Japan.
Department of Pathology, Tohoku Medical and Pharmaceutical University School of Medicine, 981-8558 Sendai, Japan.
Int J Mol Sci. 2018 Feb 18;19(2):609. doi: 10.3390/ijms19020609.
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.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药性是肺癌治疗中最重要的问题之一。有报道称，对 EGFR-TKI 耐药的肺腺癌比对 EGFR-TKI 敏感的癌症具有更高的侵袭和迁移能力，但 EGFR-TKI 耐药肺腺癌中基质金属蛋白酶（MMPs）的功能尚未得到探索。本研究旨在阐明 MMP-1 在 EGFR-TKI 耐药肺腺癌中的意义。通过使用 EGFR-TKI 敏感和耐药细胞系进行迁移和侵袭实验的体外研究以及使用 EGF 和雷帕霉素进行磷酸化抗体阵列的研究，我们首先证明，MMP-1 的过表达可能是哺乳动物雷帕霉素靶蛋白（mTOR）途径激活的结果，在 EGFR-TKI 耐药肺腺癌的迁移和侵袭能力中发挥重要作用。此外，使用 89 例肺腺癌的免疫组织化学研究表明，MMP-1 的高表达与不良预后以及吸烟史和侵袭性黏液性腺癌亚型等因素显著相关。这些结果与该体外研究的结果一致。总之，本研究为开发可能的替代治疗方法提供了思路，即通过操纵 MMP-1 和 EGFR-TKI 耐药肺腺癌中的 mTOR 信号通路。
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