title: Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFβ signaling.
abstract: Epithelial mesenchymal transition (EMT) is considered to be correlated with malignancy of cancer cells and responsible for cancer invasion and metastasis. We previously reported that distant metastasis was associated with hypoxia in gastric cancer. We therefore investigated the effect of hypoxic condition on EMT of gastric cancer cells. Gastric cancer cells were cultured in normoxia (21% O2) or hypoxia (1% O2) for 24 h. EMT was evaluated as the percentage of spindle-shaped cells in total cells. Effect of transforming growth factor β1 (TGFβ1) or tyrosine kinase inhibitors on the EMT was evaluated. The expression level of TGFβ1 and TGFβR was evaluated by real time RT-PCR. The TGFβ1 production from cancer cells was measured by ELISA. Hypoxia stimulated EMT of OCUM-2MD3 and OCUM-12 cells, but not that of OCUM-2M cells. The expression level of TGFβ1 mRNA under hypoxia was significantly higher than that under normoxia in all of three cell lines. The expression level of TGFβR mRNA was significantly increased by hypoxia in OCUM-2MD3 cells, but not in OCUM-2M cells. TGFβR inhibitor, SB431542 or Ki26894, significantly suppressed EMT of OCUM-2MD3 and OCUM-12. TGFβ1 production from OCUM-2MD3 and OCUM-12 cells was significantly increased under hypoxia in comparison with that under normoxia. These findings might suggest that hypoxia stimulates the EMT of gastric cancer cells via autocrine TGFβ/TGFβR signaling.
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuoka
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Doi
authors.forename: Yuhiko
authors.initials: Y
authors.lastname: Fuyuhiro
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Kato
authors.forename: Osamu
authors.initials: O
authors.lastname: Shinto
authors.forename: Satoru
authors.initials: S
authors.lastname: Noda
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kashiwagi
authors.forename: Naoki
authors.initials: N
authors.lastname: Aomatsu
authors.forename: Toshiki
authors.initials: T
authors.lastname: Hirakawa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Shimizu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miwa
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yamada
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sawada
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
mesh_terms: D000704:Analysis of Variance; D019898:Autocrine Communication / Q000502:physiology*; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1