The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers
Enrique Zudaire, … , Michael Birrer, Frank Cuttitta
Enrique Zudaire, … , Michael Birrer, Frank Cuttitta
Published January 2, 2008
Citation Information: J Clin Invest. 2008;118(2):640-650. https://doi.org/10.1172/JCI30024.
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The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers

Abstract

The aryl hydrocarbon receptor repressor (AHRR) is a bHLH/Per-ARNT-Sim transcription factor located in a region of chromosome 5 (5p15.3) that has been proposed to contain one or more tumor suppressor genes. We report here consistent downregulation of AHRR mRNA in human malignant tissue from different anatomical origins, including colon, breast, lung, stomach, cervix, and ovary, and demonstrate DNA hypermethylation as the regulatory mechanism of AHRR gene silencing. Knockdown of AHRR gene expression in a human lung cancer cell line using siRNA significantly enhanced in vitro anchorage-dependent and -independent cell growth as well as cell growth after transplantation into immunocompromised mice. In addition, knockdown of AHRR in non-clonable normal human mammary epithelial cells enabled them to grow in an anchorage-independent manner. Further, downregulation of AHRR expression in the human lung cancer cell line conferred resistance to apoptotic signals and enhanced motility and invasion in vitro and angiogenic potential in vivo. Ectopic expression of AHRR in tumor cells resulted in diminished anchorage-dependent and -independent cell growth and reduced angiogenic potential. These results therefore demonstrate that AHRR is a putative new tumor suppressor gene in multiple types of human cancers.

Authors

Enrique Zudaire, Natalia Cuesta, Vundavalli Murty, Karen Woodson, Lisa Adams, Nieves Gonzalez, Alfredo Martínez, Gopeshwar Narayan, Ilan Kirsch, Wilbur Franklin, Fred Hirsch, Michael Birrer, Frank Cuttitta

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Figure 3

Effects of siRNA-induced silencing of AHRR.

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Effects of siRNA-induced silencing of AHRR. (A) A549E (b...
(A) A549E (black bars), A549F (white bars), and A549G (gray bars) were incubated in serum-free media (R0) or the appropriate media containing α-Fas or MK886. In all experiments (n = 3), A549F/G showed enhanced resistant to proapoptotic signals when compared with A549E. (B) DIVAA analysis showed that A549F and A549G have enhanced angiogenic potential when compared with A549E, and this effect was more prominent for A549G than for A549F (n = 8). (C) Silencing of AHRR (A549F/G) enhances the migratory (black bars) and invasive (white bars) potential of the A549 tumor cell line (n = 6). Detail photos of the porous membranes used to determine migratory potential of A549E and A549G are also shown. Original magnification, ×10. *P < 0.05; **P < 0.01; ***P < 0.001.