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.

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

“…Furthermore, HIFIA knockdown might downregulate the expression of LOX. In contrast, it has been reported that LOX is regulated by TGFb signaling [55] which is upreglated in hypoxic conditions [36], which suggests that TGFb is also associated with LOX mRNA expression in hypoxic conditions.…”

“…Hypoxic conditions could affect the EMT of gastric cancer cells. We previously reported that hypoxia stimulated EMT of OCUM-2MD3 and OCUM-12 cells, and that TGFb receptor (TGFbR) inhibitor partially suppressed the EMT of OCUM-2MD3 and OCUM-12 cells [36], which suggests that there exists another factor, besides TGFb/TGFbR signaling, responsible for the EMT of cancer cells in hypoxia. In this study, we found that not only TGFb signaling but also LOX affects the EMT of gastric cancer cells under hypoxic conditions.…”

“…resulting in a highly invasive form of gastric cancer in vitro and that transforming growth factor b (TGFb) is one of the factors regulating EMT under hypoxia [36,37]. However, the mechanisms of EMT under hypoxic conditions have not been fully revealed, and we speculated LOX is associated with gastric cancer progression in a hypoxic environment.…”

Hepatocyte growth factor increases the invasive potential of PC-3 human prostate cancer cells via an ERK/MAPK and Zeb-1 signaling pathway

“…Numerous factors induce EMT, including transforming growth factor-β (TGF-β), epidermal growth factor (EGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), platelet-derived growth factor, insulin-like growth factor (IGF) (11), hypoxia (11,12) and micro RNA (13). These factors induce EMT via various signaling pathways, including Wnt, Hedgehog and Notch (14,15).…”

A circulating tumor cell cluster-based model for tumor metastasis (Hypothesis)

“…Numerous changes occur under these conditions. Embolism or complete thrombosis in microvessels can cause local hypoxia, which has been proven to induce EMT in various cancers, including hepatocellular carcinoma, gastric cancer, pancreatic cancer, breast cancer and colon cancer (37)(38)(39)(40)(41). EMT of CTCs may contribute to tumor cell extravasation from vessels into tissues.…”