Our study demonstrates that RAI3 expression was unrelated to clinic-pathological features of NSCLCs and survival of patients. Thus, RAI3 expression cannot be considered as prognostic marker in lung cancer patients.
In the present study, lung cancers had lower levels of RAI3 immunostaining than normal bronchial epithelia. This result is in line with previous studies analyzing RAI3 expression in cohorts of 150 and 474 NSCLC patients (Lin et al. 2014) (Fujimoto et al. 2012). The functional relevance of RAI3 expression in benign lung was previously highlighted by earlier studies demonstrating that GPRC5A-knockout mice spontaneous develop lung adenomas and adenocarcinomas (Tao et al. 2007) and that loss of heterozygosity of chromosome 12p13 is a common alteration in NSCLCs (Takeuchi et al. 1996) (Grepmeier et al. 2005). Taken together, it is tempting to suggest that GPRC5A might have a tumor-suppressive function in lung epithelial cells.
Within NSCLC subtypes, RAI3 expression was significantly decreased in LCLCs and SQCCs relative to LUACs. This observation is in accordance with the study of Fujimoto et al. (Fujimoto et al. 2012) on RAI3 expression in a cohort of 474 NSCLC patients, describing a positive association between RAI3 expression and LUAC histology (Fujimoto et al. 2012). Moreover, Fujimoto et al. (Fujimoto et al. 2012) suggested that RAI3 expression was highest in disease-free lung, decreased and intermediate in lung of cancer-free COPD patients and further attenuated and lowest in epithelia of COPD patients with LUAC and SQCC histology. These findings pinpoint to a potential tumor-suppressive role, similar to that established in mice, of GPRC5A in the sequential development of human NSCLC, in particular those associated with inflammatory chronic obstructive disease which is a major risk factor for lung cancer and shares various pathogenic features with lung tumor (Wistuba and Gazdar 2006).
The mechanism how RAI3 drives lung carcinogenesis remains elusive. Interestingly, GPRC5A-knockout mice developed LUACs and not LCLCs and SQCCs (Tao et al. 2007). These findings may be due to biological pathway-specific gene signatures that are differentially expressed and relevant in distinct subtypes of NSCLC. Previous microarray analysis showed that the transcriptomes of lung epithelial cells of GPRC5A-knockout defined a loss-of-GPRC5A gene signature, which was characterized by many aberrations in cancer-associated pathways, and was prevalent in human LUACs compared with SQCCs or normal lung (Wistuba and Gazdar 2006).
In literature, RAI3 has been suggested as prognostic marker in several cancer types, including colon cancer (Kume et al. 2014) (Zougman et al. 2013), gastric cancer (Cheng et al. 2012), oral squamous cell carcinoma(Liu et al. 2013), and hepatocellular carcinoma (Zheng et al. 2014). However, our study shows that RAI3 protein expression in unrelated to clinical outcome of patients in a large cohort of more than 600 NSCLCs.
In summary, our study excludes RAI3 as prognostic marker but underlines the potential role of RAI3 as tumor suppressor in lung cancer.