The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers
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
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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Research Article Oncology

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 1

AHRR mRNA expression levels in tumors and normal controls as assessed by real-time PCR.

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AHRR mRNA expression levels in tumors and normal controls as assessed b...
(A) Significant downregulation in AHRR mRNA (between 30% and 90%) was observed in tumors from several origins. Data are presented as a ratio of mRNA levels in tumor versus normal control. (B) Primary colon tumors showed a very strong downregulation of AHRR mRNA when compared with normal controls. Interestingly, nonmalignant colon polyps exhibited a more moderate downregulation of AHRR mRNA when compared with colon tumors. Statistically significant differences were achieved when comparing levels of AHRR in normal tissue with levels in polyps. (C) AHRR expression levels in normal cervical tissue, cervical tumor cell lines, and primary cervical tumors. Strong downregulation or complete ablation of AHRR mRNA was observed in 100% of cell lines and 80% of the primary tumors when compared with normal controls. Little variation was observed in the levels of AHRR mRNA among the normal controls. (D) All ovarian tumor cell lines included in this study showed downregulation of AHRR mRNA levels when compared with normal ovarian cell lines. (E) Box-and-whisker plot showing significant downregulation AHRR mRNA levels observed in lung tumors and normal tissues from the same patients. ***P < 0.001.