GPCR5A was identified as a retinoic acid (RA) inducible gene with homology to type 3 G-protein coupled receptor family. It is expressed primarily in normal lung epithelial tissue, but low levels were also detected in other epithelial tissues. Because RA has shown activity as chemopreventive and therapeutic agent, we speculated that GPCR5A acts as a mediator of some of these effects. To further explore the role of GPCR5A in cancer development, we analyzed its expression in 75 human cancer cell lines including: 13 non-small cell lung cancer (NSCLC), 6 head and neck squamous cell carcinoma, 12 breast carcinoma, 4 prostatic carcinoma, 2 melanomas, 3 cervical carcinoma, 10 teratocarcinoma, 17 colon carcinoma, 3 gastric carcinoma, 2 glioblastoma, and 3 bladder carcinomas and its induction by RA and fenretinide (4HPR) in most of these cell lines using northern blotting. The constitutive expression of GPCR5A varied greatly among those cell lines; 18 of 75 (24%) cancer cell lines had undetectable levels, 26/75 (35%) exhibited a low expression, 13/75 (17%) had moderate, and 18/75 (24%) had high expression relative to GAPDH. When treated with RA and /or 4HPR, most cell lines with undetectable to moderate expression showed induction or further increase of GPCR5A. In contrast, all cell lines with high expression didn’t show any changes. The constitutive expression of GPCR5A in 10 of 14 (71%) human lung and head neck cancer cell lines was undetectable to moderate but could be induced by RA and/or 4HPR. Further analyses of RNA isolated from paired human normal and malignant lung tissues from 18 NSCLC patients demonstrated that 11/18 (61%) cases had a lower level of GPCR5A mRNA in the tumor relative to the normal, 2/18 (11%) pairs had higher level of GPCR5A in tumor relative to normal, one case had similar levels in tumor and normal and in 4 cases GPCR5A was undetectable. These results indicate that a considerable proportion of human NSCLC has decreased level of GPCR5A. In silico analysis of published data on gene expression in a large collection of human lung tissues, including 17 adjacent normal lung tissues, 139 adenocarcinomas, 21 squamous cell carcinomas, 6 small cell lung cancers, and 20 carcinoid tumors revealed that GPCR5A expression was significantly lower in all types of lung cancer compared with normal lung tissues. In conclusion, the constitutive expression of GPCR5A was low in the majority of human cancer cell lines and could be induced by RA and/or 4HPR in many of these cells. Furthermore, the expression of GPCR5A appears to be low in the majority of human lung cancer tissues than in adjacent normal tissues, supporting a possible role of GPCR5A as tumor suppressor as demonstrated previously in a knockout mouse model. Supported by the Samuel Waxman Cancer Research Foundation.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]