Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFβ signaling.
Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFβ signaling.
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DOI：
10.1371/journal.pone.0062310
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hirakawa K
中科院分区：
文献类型：
--
作者：
Matsuoka J;Yashiro M;Doi Y;Fuyuhiro Y;Kato Y;Shinto O;Noda S;Kashiwagi S;Aomatsu N;Hirakawa T;Hasegawa T;Shimizu K;Shimizu T;Miwa A;Yamada N;Sawada T;Hirakawa K
上皮间充质转化（Epithelial mesenchymal transition， EMT）被认为与癌细胞的恶性相关，并与癌症的侵袭和转移有关。我们以前报道过胃癌的远端转移与缺氧有关。因此，我们研究了缺氧条件对胃癌细胞EMT的影响。胃癌细胞在常氧（21% O2）或缺氧（1% O2）条件下培养24 h。EMT以梭形细胞占总细胞的百分比计算。观察转化生长因子β1 （tgf - β1）或酪氨酸激酶抑制剂对EMT的影响。实时RT-PCR检测tgf - β1和tgf - β r的表达水平。ELISA法检测癌细胞tgf - β1的产生。缺氧刺激OCUM-2MD3和OCUM-12细胞的EMT，但对OCUM-2M细胞没有刺激作用。tgf - β1 mRNA在缺氧条件下的表达量均显著高于常氧条件下的表达量。缺氧可显著提高OCUM-2MD3细胞中tgf - β r mRNA的表达水平，而OCUM-2M细胞中tgf - β r mRNA的表达水平无明显变化。TGFβR抑制剂SB431542或Ki26894显著抑制OCUM-2MD3和OCUM-12的EMT。低氧条件下OCUM-2MD3和OCUM-12细胞tgf - β1的产生明显高于常氧条件下。这些发现可能提示缺氧通过自分泌TGFβ/TGFβ r信号刺激胃癌细胞的EMT。
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.
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