Research Papers:

Deficiency of protein-L-isoaspartate (D-aspartate) O-methyl-transferase expression under endoplasmic reticulum stress promotes epithelial mesenchymal transition in lung adenocarcinoma

Masahiro Yamashita _, Masahito Ogasawara, Yasushi Kawasaki, Miyuki Niisato, Heisuke Saito, Shuya Kasai, Chihaya Maesawa, Makoto Maemondo and Kohei Yamauchi

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Oncotarget. 2018; 9:13287-13300. https://doi.org/10.18632/oncotarget.24324

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Masahiro Yamashita1, Masahito Ogasawara2, Yasushi Kawasaki3, Miyuki Niisato1, Heisuke Saito1, Shuya Kasai4,5, Chihaya Maesawa4, Makoto Maemondo1 and Kohei Yamauchi1,6

1Department of Pulmonary Medicine, Allergy and Immunological Diseases, School of Medicine, Iwate Medical University, Morioka, Iwate, Japan

2Department of Pharmacology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan

3Department of Health Chemistry, School of Pharmacology, Iwate Medical University, Shiwa, Iwate, Japan

4Department of Cancer Biology, Iwate Medical University, Shiwa, Iwate, Japan

5Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan

6Geriatric Health Services Facilities, Keiyu, Morioka, Japan

Correspondence to:

Masahiro Yamashita, email: [email protected]

Keywords: lung adenocarcinoma; PIMT; endoplasmic reticulum stress; epithelial mesenchymal transition; hypoxia-inducible factor 1α

Received: August 01, 2016     Accepted: January 19, 2018     Published: January 27, 2018


A prognostic association between the novel chaperone protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT) and lung adenocarcinoma has recently been reported. Here, we evaluated the functional roles of PIMT in the progression of lung adenocarcinoma. PIMT expression was detectable in 6 lung adenocarcinoma cell lines: A549, H441, H460, H1650, Calu 1, and Calu 6 cell lines. In A549 and H441 cells, knockdown by PIMT using silencing RNA of PIMT (si-PIMT) and/or small hairpin-RNA (sh-PIMT) induced a decrease in the expression of E-cadherin with an increase in vimentin expression, indicating that the epithelial to mesenchymal transition (EMT) was induced. Cell mobility, including migration and invasion capability, was increased in sh-PIMT A549 stable and si-PIMT H441 cells compared to in control cells. Endoplasmic reticulum (ER) stress, such as Thapsigargin (Tg) stress and hypoxia, induced EMT in A549 cells but not in other cell types, with an increase in GRP78 expression, whereas overexpression of PIMT reduced the EMT and cell invasion under stress conditions. The expression of hypoxia inducible factor-1 alpha (HIF1α) and Twist increased in sh-PIMT A549 and si-PIMT H441 cells, and Tg stress increased HIF1α expression levels in A549 cells in a dose-dependent manner. Moreover, LW6, an HIF1α inhibitor, reduced EMT, cancer invasion, and the levels of Twist in sh-PIMT A549 cells. Our results indicate that deficiency of supplemental PIMT expression under ER stress facilitates EMT and cell invasion in some cell types of lung adenocarcinoma.

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