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

Chi Ruei Huang, Chung Ta Lee, Kwang Yu Chang, Wen Chang Chang, Yao Wen Liu, Jenq Chang Lee, Ben Kuen Chen

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11530-11546
Number of pages17
JournalOncotarget
Volume6
Issue number13
DOIs
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology

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