CONTEXT: Colorectal cancer (CRC) is a leading cause of cancer death in recent years. It is believed that there are hypoxic regions in both early and advanced stage of tumor and hypoxia is able to reinforce the aggressiveness of tumor cells and accelerate the progression of cancer. OBJECTIVE: Until now the mechanisms by which hypoxia promotes the progression of CRC are far from well understood. Integrin-linked kinase (ILK) is a crucial mediator and over-expressed in CRC patients. But whether ILK is involved in the process that hypoxia promotes CRC cells growth and silencing the ILK gene results in CRC cells apoptosis is not clear. MATERIALS AND METHODS: Lentivirus transfection, invasion assay, TUNEL assay, Bromodeoxyuridine incorporation and mitochondrial function assay were applied to demonstrate our hypothesis. RESULTS: In this study, we found that hypoxia induced the expression of ILK in a time-dependent manner, and after knocking down ILK expression with ILK shRNA, the cells proliferation promoted by hypoxia was inhibited in HT29 cell line. Moreover, blocking the ILK pathway led to caspase-3 and caspase-9 activations, the decrease of mitochondrial membrane potential, and cells apoptosis. And the inhibitory effects of hypoxia on cells apoptosis were mediated by the ILK pathway. In addition, hypoxia promoted HT29 cells metastasis and invasion through the ILK pathway. CONCLUSIONS: Therefore, we conclude that the CRC cells survival and invasion enhanced by hypoxia are mediated by ILK, and ILK may be an important potential therapeutic target for CRC.
CONTEXT: Colorectal cancer (CRC) is a leading cause of cancer death in recent years. It is believed that there are hypoxic regions in both early and advanced stage of tumor and hypoxia is able to reinforce the aggressiveness of tumor cells and accelerate the progression of cancer. OBJECTIVE: Until now the mechanisms by which hypoxia promotes the progression of CRC are far from well understood. Integrin-linked kinase (ILK) is a crucial mediator and over-expressed in CRC patients. But whether ILK is involved in the process that hypoxia promotes CRC cells growth and silencing the ILK gene results in CRC cells apoptosis is not clear. MATERIALS AND METHODS: Lentivirus transfection, invasion assay, TUNEL assay, Bromodeoxyuridine incorporation and mitochondrial function assay were applied to demonstrate our hypothesis. RESULTS: In this study, we found that hypoxia induced the expression of ILK in a time-dependent manner, and after knocking down ILK expression with ILK shRNA, the cells proliferation promoted by hypoxia was inhibited in HT29 cell line. Moreover, blocking the ILK pathway led to caspase-3 and caspase-9 activations, the decrease of mitochondrial membrane potential, and cells apoptosis. And the inhibitory effects of hypoxia on cells apoptosis were mediated by the ILK pathway. In addition, hypoxia promoted HT29 cells metastasis and invasion through the ILK pathway. CONCLUSIONS: Therefore, we conclude that the CRC cells survival and invasion enhanced by hypoxia are mediated by ILK, and ILK may be an important potential therapeutic target for CRC.
Authors: Mei-Fong Pang; Michael J Siedlik; Siyang Han; Melody Stallings-Mann; Derek C Radisky; Celeste M Nelson Journal: Cancer Res Date: 2016-08-08 Impact factor: 12.701