The correlation of p22phox and chemosensitivity in EGFR-TKI resistant lung adenocarcinoma
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Masayuki Kobayashi1, Ryoko Saito1, Yasuhiro Miki1, Ren Nanamiya1, Chihiro Inoue1, Jiro Abe2, Ikuro Sato3, Yoshinori Okada4 and Hironobu Sasano1
1Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan
2Department of Thoracic Surgery, Miyagi Cancer Center, Miyagi, Japan
3Department of Pathology, Miyagi Cancer Center, Miyagi, Japan
4Department of Thoracic Surgery, Tohoku University Hospital, Miyagi, Japan
Ryoko Saito, email: [email protected]
Keywords: EGFR-TKI resistance; chemoresistance; p22phox; HIF-1α; EMT
Received: November 10, 2018 Accepted: January 12, 2019 Published: February 01, 2019
Background: Enhancing the chemosensitivity in the patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistant lung adenocarcinoma (LUAD) is pivotal in achieving their successful therapeutic outcome. We aimed to explore the mechanisms regarding the development of therapeutic resistance to chemotherapy in EGFR-TKI resistant LUAD. Methods: Microarray analysis lead to potential involvement of p22phox, which was abundantly expressed in the cell lines harboring EGFR-TKI resistance and chemoresistance, and was known to regulate several important chemoresistance-associated factors such as hypoxia inducible factor-1α (HIF-1α) and epithelial-mesenchymal transition (EMT). We compared the status of p22phox with that of chemoresistance, HIF-1α expression and EMT in LUAD cell lines. We immunolocalized p22phox in the specimens of lung cancer patients.
Results: p22phox and HIF-1α mRNAs were significantly elevated in the cells harboring EMT and chemoresistance. p22phox knockdown enhanced chemosensitivity and reduced the expression of HIF-1α and EMT-associated factors. HIF-1α knockdown enhanced the chemosensitivity, while HIF-1α transfection induced EMT and chemoresistance in these cell lines. All LUAD patients with T790M mutation were associated with abundant p22phox immunoreactivity in carcinoma cells.
Conclusions: The analysis of p22phox in lung carcinoma tissues could provide new insights into the selection of chemotherapy for the patients with EGFR-TKI resistant LUAD.
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