Role of Bitter Taste Receptor TAS2R38 In Colorectal Cancer

Colorectal cancer (CRC) is a leading cause of cancer‐related deaths in the United States with 53,200 deaths projected in 2020. Although methods to detect CRC are available, it remains a major problem and is a leading cause of cancer‐related deaths. Hence, there is a dire need to identify novel signaling pathways as targets for therapy. Based on a bedside observation where CRC patients complained about dysgeusia or taste alterations even before being discovered with cancer, we looked at the expression of the 25 bitter taste receptors (TAS2R1‐50, TAS2R60). In addition to the oral activity, these receptors are found in the lung, the heart, thyroid, and gastrointestinal muscles. Taste receptors utilize G‐protein coupled receptors (GPCRs) and signal through G‐βγ activation of PLCβ2, IP3‐mediated release of Ca2+ and activation of TRPM5, leading to the release of ATP as a transmitter to activate gustatory afferents. Recently, a few TAS2 receptors have been shown to be upregulated in various cancers, but nothing is known about their expression in CRC. Hence, we first started by mining the Cancer Genome Atlas (TCGA) database. In TCGA, we observed that TAS2R38 is upregulated in 16 different cancers, including CRC. Moreover, higher expression of the TAS2R38 correlated with lower overall survival in CRC patients. We confirmed TAS2R38 overexpression in CRC tissues and cell lines by immunohistochemistry and RT‐PCR. Also, in the functional assay, N‐(3‐oxododecanoyl)‐L‐homoserine lactone (OdDHL), a TAS2R38 agonist, treatment activated calcium mobilization in HCT116 and DLD1 cells. OdDHL also increased interleukin (IL)‐6 and IL‐8 mRNA levels in the CRC cell lines. To determine whether expression of the receptor is affected in vivo, we performed studies in the dextran sodium sulfate (DSS)‐induced acute colitis model and colitis‐associated cancer model (azoxymethane (AOM)‐DSS) in C57BL/6 mice. TAS2R138, the murine homolog of human TAS2R38 is upregulated in crypt epithelial cells in both the DSS‐induced acute colitis and AOM/DSS tumors. The tumor microenvironment plays an important role in CRC progression. The immune cell infiltration in the CRC tumor is heterogenous. Macrophages, dendritic cells, neutrophils and lymphocytes, such as T cells have been studied in CRC and different populations of these cells were reported to control tumor progression. We found that TAS2R138 mRNA is increased in F4/80‐positive macrophages, CD11c‐positive dendritic cells and Ly6G‐positive neutrophils in the DSS‐induced acute colitis model. Immunofluorescence analysis of tissues from AOM/DSS induced tumors showed that TAS2R38 colocalizes with F4/80 macrophages suggesting that these cells express TAS2R138. Similar colocalization of TAS2R138 was found with Ly6G and CD11c. These observations suggest that TAS2R38 may play a critical role in CRC progression in part by modulating immune cells.