Role of ADAM17 in invasion and migration of CD133-expressing liver cancer stem cells after irradiation
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Sung Woo Hong1, Wonhee Hur1, Jung Eun Choi1, Jung-Hee Kim1, Daehee Hwang2, Seung Kew Yoon1
1The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
2Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu, Republic of Korea
Seung Kew Yoon, e-mail: firstname.lastname@example.org
Keywords: cancer stem cells, hepatocellular carcinoma, radioresistance, ADAM17, migration
Received: August 20, 2015 Accepted: February 28, 2016 Published: March 16, 2016
We investigated the biological role of CD133-expressing liver cancer stem cells (CSCs) enriched after irradiation of Huh7 cells in cell invasion and migration. We also explored whether a disintegrin and metalloproteinase-17 (ADAM17) influences the metastatic potential of CSC-enriched hepatocellular carcinoma (HCC) cells after irradiation. A CD133-expressing Huh7 cell subpopulation showed greater resistance to sublethal irradiation and specifically enhanced cell invasion and migration capabilities. We also demonstrated that the radiation-induced MMP-2 and MMP-9 enzyme activities as well as the secretion of vascular endothelial growth factor were increased more predominantly in Huh7CD133+ cell subpopulations than Huh7CD133− cell subpopulations. Furthermore, we showed that silencing ADAM17 significantly inhibited the migration and invasiveness of enriched Huh7CD133+ cells after irradiation; moreover, Notch signaling was significantly reduced in irradiated CD133-expressing liver CSCs following stable knockdown of the ADAM17 gene. In conclusion, our findings indicate that CD133-expressing liver CSCs have considerable metastatic capabilities after irradiation of HCC cells, and their metastatic capabilities might be maintained by ADAM17. Therefore, suppression of ADAM17 shows promise for improving the efficiency of current radiotherapies and reducing the metastatic potential of liver CSCs during HCC treatment.
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