CSIG-41. UPREGULATED EXPRESSION OF THE ARYL HYDROCARBON RECEPTOR PATHWAY IN BRAIN METASTASES FROM MALIGNANT MELANOMA

Abstract

OBJECTIVE

The Aryl-hydrocarbon-receptor (AHR) is a ligand activated transcription factor linked to exogenic carcinogenic agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 2011, the tryptophan (TRP) catabolite kynurenine (KYN) was identified as an endogenous ligand for AHR. The AHR is involved in several crucial processes such as cell migration, tumorigenesis, and immune function. Dysregulation of AHR, its nuclear translocator (ARNT), its repressor AHRR and the KYN building Enzyme TRP-2,3-dioxygenase 2 (TDO) has been linked to poor survival in patients with Glioblastoma. We aimed to evaluate the AHR-pathway in brain metastases.

METHODS

Using qRT-PCR, gene expression was analyzed in 19 brain-metastases of melanoma patients, 10 control tissues from peritumoral brain and 10 glioblastoma (GBM) samples. Differences in the expression of AHR, ARNT, AHRR, TDO as well as the AHR/AHRR ratio between tumor tissue and control were analyzed. Results are depicted in mean values with standard deviation (SD) and in Arbitrary Units (AU). p<.05 was considered significant.

RESULTS

Both, AHR and ARNT were massively overexpressed in metastatic tissues (p<.01) (6- and 4.5-fold) in comparison to control (AHR: 3.64 ± 2.32 vs. .58 ±.50; p<0.01 and ARNT: 3.81 ± 2.25 vs. .83 ±.48, p<.01). AHRR and TDO where not significantly upregulated (.73 ±.88 vs. .41 ±.35; p=.31 and .37 ±.61 vs. .14 ±.09; p=.46). The ratio of AHR and its repressor AHRR (AHRR/AHR) was significantly different between metastases and control, hinting at a distinct regulatory imbalance (.55 ± 1.09 vs. .18 ± 1.60 p<.01). The difference of AHR expression in metastases and GBM did not quite reach significance (3.64 ± 2.32 vs. 1.27 ± 1.89; p=.055). ARNT was significantly elevated in metastases compared to GBM (3.81 ± 2.25 vs. 1.7 ±.1.15, p<.01).

CONCLUSION

The AHR pathway is significantly upregulated in melanoma brain metastases and might play a pathophysiological role in growth and progression of brain metastases.