Retinoid Receptors in Gastric Cancer: Expression and Influence on Prognosis

Background: Gastric cancer is frequently lethal despite aggressive multimodal therapies, and new treatmentapproaches are therefore needed. Retinoids are potential candidate drugs: they prevent cell differentiation,proliferation and malignant transformation in gastric cancer cell lines. They interact with nuclear retinoidreceptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcriptionfactors, each with three subclasses, α, β and γ. At present, little is known about retinoid expression and influenceon prognosis in gastric cancers. Patients and
Methods: We retrospectively analyzed the expression of thesubtypes RARa, RARβ, RARγ, RXRa, RXRβ, RXRγ by immunohistochemistry in 147 gastric cancers and 51normal gastric epithelium tissues for whom clinical follow-up data were available and correlated the resultswith clinical characteristics. In addition, we quantified the expression of retinoid receptor mRNA using realtimePCR (RT-PCR) in another 6 gastric adenocarcinoma and 3 normal gastric tissues. From 2008 to 2010, 80patients with gastric cancers were enrolled onto therapy with all-trans-retinoic acid (ATRA).
Results: RARa,RARβ, RARγand RXRγ positively correlated with each other (p < 0.001) and demonstrated significantly lowerlevels in the carcinoma tissue sections (p < 0.01), with lower RARβ, RARγ and RXRa expression significantlyrelated to advanced stages (p < =0.01). Tumors with poor histopathologic grade had lower levels of RARa andRARβ in different histological types of gastric carcinoma (p < 0.01). Patients whose tumors exhibited low levelsof RARa expression had significantly lower overall survival compared with patients who had higher expressionlevels of this receptor (p < 0.001, HR=0.42, 95.0% CI 0.24-0.73), and patients undergoing ATRA treatment hadsignificantly longer median survival times (p = 0.007, HR=0.41, 95.0% CI 0.21-0.80).
Conclusions: Retinoicacid receptors are frequently expressed in epithelial gastric cancer with a decreased tendency of expression andRARa may be an indicator of a positive prognosis. This study provides a molecular basis for the therapeutic useof retinoids against gastric cancer.