{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:29:36Z","timestamp":1793140176831,"version":"4.5.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Gastric cancer is a heterogeneous collection of tumors characterized by low survival rates. All-trans retinoic acid (retinoic-acid) is a clinically useful therapeutic agent belonging to the chemical family of retinoids, which consists of both natural and synthetic derivatives of vitamin-A. Retinoids are essential components of the normal diet and they regulate different physiological processes. From a therapeutic point of view, retinoic-acid is the first example of clinically useful differentiating agent. Indeed, the differentiating properties of this compound have promoted the use of retinoic-acid as a standard of care in Acute-Promyelocytic-Leukemia, a rare form of acute myeloid leukemia. In this study, we determine the RNA expression of the six isoforms of <jats:italic>Retinoic<\/jats:italic>-<jats:italic>Acid<\/jats:italic>-<jats:italic>Receptors<\/jats:italic> (<jats:italic>RAR\u03b1<\/jats:italic>\/<jats:italic>RAR\u03b2<\/jats:italic>\/<jats:italic>RAR\u03b3<\/jats:italic>\/<jats:italic>RXR\u03b1<\/jats:italic>\/<jats:italic>RXR\u03b2<\/jats:italic>\/<jats:italic>RXR\u03b3<\/jats:italic>) in view of their potential use as gastric cancer progression markers and\/or therapeutic targets. In addition, we evaluate associations between the expression of these receptors and a simplified molecular classification of stomach tumors as well as the clinical characteristics of the cohort of patients analyzed. Finally, we define the prognostic value of the various <jats:italic>Retinoic<\/jats:italic>-<jats:italic>Acid<\/jats:italic>-<jats:italic>Receptors<\/jats:italic> in gastric cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this single institution and retrospective <jats:italic>RAR-GASTRIC<\/jats:italic> study, we consider 55 consecutive gastric cancer patients. We extract total RNA from the pathological specimens and we perform a <jats:italic>NanoString Assay<\/jats:italic> using a customized panel of genes. This allows us to determine the expression levels of the <jats:italic>RAR<\/jats:italic> and <jats:italic>RXR<\/jats:italic> mRNAs as well as other transcripts of interest.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our data demonstrate ubiquitous expression of the <jats:italic>RAR<\/jats:italic> and <jats:italic>RXR<\/jats:italic> mRNAs in gastric cancers. High levels of <jats:italic>RAR\u03b1<\/jats:italic>, <jats:italic>RAR\u03b2<\/jats:italic>, <jats:italic>RXR\u03b1<\/jats:italic> and <jats:italic>RXR\u03b2<\/jats:italic> show a significant association with stage IV tumors, \u201c<jats:italic>de novo<\/jats:italic>\u201d metastatic disease, microsatellite-stable-status, epithelial-to-mesenchymal-transition, as well as <jats:italic>PIK3CA<\/jats:italic> and <jats:italic>TP53<\/jats:italic> expression. Finally, we observe a worse <jats:italic>overall<\/jats:italic>-<jats:italic>survival<\/jats:italic> in gastric cancer patients characterized by high <jats:italic>RAR\u03b1<\/jats:italic>\/<jats:italic>RAR\u03b2<\/jats:italic>\/<jats:italic>RAR\u03b3<\/jats:italic>\/<jats:italic>RXR\u03b2<\/jats:italic> mRNA levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In gastric cancer, high expression levels of <jats:italic>RAR\u03b1<\/jats:italic>\/<jats:italic>RAR\u03b2<\/jats:italic>\/<jats:italic>RAR\u03b3<\/jats:italic>\/<jats:italic>RXR\u03b2<\/jats:italic> transcripts are associated with poor clinical and molecular characteristics as well as with reduced <jats:italic>overall<\/jats:italic>-<jats:italic>survival<\/jats:italic>. Our data are consistent with the idea that <jats:italic>RAR\u03b1<\/jats:italic>, <jats:italic>RAR\u03b2<\/jats:italic>, <jats:italic>RAR\u03b3<\/jats:italic> and <jats:italic>RXR\u03b2<\/jats:italic> represent potential prognostic markers and therapeutic targets of gastric cancer.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2024.1453934","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T04:24:29Z","timestamp":1726028669000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["The potential of retinoic acid receptors as prognostic biomarkers and therapeutic targets in gastric cancer"],"prefix":"10.3389","volume":"14","author":[{"given":"Silvio 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