Down-regulation of ARNT promotes cancer metastasis by activating the fibronectin/integrin β1/FAK axis.

Abstract

The aryl hydrocarbon receptor nuclear translocator (ARNT) is broadly involved in regulating tumorigenesis by inducing genes that are involved in tumor growth and angiogenesis. Tumorigenesis usually involves normoxic conditions. However, the role of ARNT in tumor metastasis during normoxia remains unclear. Here, we demonstrate that ARNT protein levels were decreased in late-stage human colorectal cancer using immunohistochemical analysis. Down-regulation of ARNT protein promoted cancer cell migration and invasion, which was mediated by activation of the fibronectin/integrin β1/FAK signaling axis. In addition, the enhancement of migration and invasion in ANRT knockdown cells was blocked when ARNT was restored in the cells. In xenografts in severe combined immunodeficiency mice, tumor growth was significantly inhibited in the ARNT-knockdown condition. However, the tail-vein injection animal model revealed that the depletion of ARNT-induced metastatic lung colonies was further enhanced when ARNT expression was recovered post-injection. Interestingly, chemotherapeutic drugs inhibited ARNT expression and promoted the invasion of residual tumor cells. These results suggest that ARNT may play a positive role during tumor growth (either in early-stage tumor growth or in organ metastases), but plays a negative role in tumor migration and invasion. Therefore, the efficiency of ARNT-targeted therapy during different cancer stages should be carefully evaluated.

• Authors: Chi-Ruei Huang, Chung-Ta Lee, Kwang-Yu Chang, Wen-Chang Chang, Yao-Wen Liu, Jenq-Chang Lee, Ben-Kuen Chen
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 13 Pg. 11530-46 (May 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25839165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARNT protein, human
• Fibronectins
• Integrin beta1
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Focal Adhesion Kinase 1
• PTK2 protein, human

Topics

• Adenocarcinoma (enzymology, genetics, secondary)
• Animals
• Aryl Hydrocarbon Receptor Nuclear Translocator (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Colonic Neoplasms (enzymology, genetics, pathology)
• Fibronectins (genetics, metabolism)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Integrin beta1 (genetics, metabolism)
• Lung Neoplasms (enzymology, genetics, secondary)
• Male
• Mice, SCID
• Neoplasm Invasiveness
• Neoplasm Staging
• RNA Interference
• Signal Transduction
• Time Factors
• Transfection