Deregulation of Trace Amine-Associated Receptors (TAAR) Expression and Signaling Mode in Melanoma

Abstract

Trace amine-associated receptors (TAARs) interact with amine compounds called “trace amines” which are present in tissues at low concentrations. Recently, TAARs expression in neoplastic tumors was reported. In this study, TAARs expression was analyzed in public RNAseq datasets in nevi and melanoma samples and compared to the expression of dopamine receptors (DRDs) that are known to be involved in melanoma pathogenesis. It was found that all DRDs and TAARs are expressed in nevi at comparable levels. Differential expression analysis demonstrated the drastic decrease of TAAR1, TAAR2, TAAR5, TAAR6, and TAAR8 expression in melanomas compared to benign nevi with only TAAR6, TAAR8, and TAAR9 remaining detectable in malignant tumors. No association of TAARs expression levels and melanoma clinicopathological characteristics was observed. TAARs co-expressed genes in melanoma and nevi were selected by correlation values for comparative pathway enrichment analysis between malignant and benign neoplasia. It was found that coexpression of TAARs with genes inquired in neurotransmitter signaling is lost in melanoma, and tumor-specific association of TAAR6 expression with the mTOR pathway and inflammatory signaling is observed. It is not excluded that TAARs may have certain functions in melanoma pathogenesis, the significance of which to tumor progression is yet to be understood.

The Expression of Trace Amine-Associated Receptors (TAARs) in Breast Cancer Is Coincident with the Expression of Neuroactive Ligand–Receptor Systems and Depends on Tumor Intrinsic Subtype

“…The analysis of the genes which are co-expressed with different TAARs identified an association with the “Olfactory transduction” pathway, especially with ORs, like it was described previously in melanoma [ 75 ]. Despite odorant receptors (ORs) primarily being identified in the olfactory epithelium, currently, these receptors were observed outside of the olfactory system in all other human tissues tested to date [ 73 , 74 ].…”

“…This is the largest gene family in the mammalian genome, and in humans, more than 400 OR genes were identified [ 76 ]. ORs are commonly overexpressed in tumor tissues, including BC, compared to adjacent noncancerous samples [ 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. Different OR expression may demonstrate various associations with tumor characteristics.…”

“…Also, in BC, all TAARs except TAAR6 were co-expressed with a variety of other neuroactive ligand-recognizing molecules. TAAR1 interactions with epinephrine [ 13 ] and 5-HT [ 15 ] signaling, which are involved in BC development and progression [ 18 , 23 , 25 , 75 , 83 , 84 , 85 , 86 , 87 ] are previously described. The co-expression of these receptors in tumors supports the possibility of modulating epinephrine and 5-HT signals in tumor tissue by TAAR1.…”

Structure-Based Discovery of Mouse Trace Amine-Associated Receptor 5 Antagonists

“…They play a critical role in detecting volatile amines associated with distinct ethological or ecological cues, and their ligands are present in decaying foods and animal body fluids as a consequence of the decarboxylation of amino acids by endogenous enzymes or through microbial metabolism . TAs mediate innate animal social communication, such as sexual attraction, predator avoidance and aversive response that are crucial for animal survival and reproduction. , Recent evidence of the presence of TAAR2–9 members in several extranasal tissues suggests their involvement in physiological processes other than olfaction. − TAAR2–9 receptors are now suggested as potential drug targets for several diseases, including food-induced inflammatory responses (e.g., Crohn′s disease, ulcerative colitis), metabolic disorders (e.g., type-2 diabetes, obesity) and even melanoma. − However, a detailed characterization of TAAR2–9 is hampered by their low expression levels and the limited number of experimentally identified ligands …”