AUTHOR=Garattini Silvio Ken , Basile Debora , De Re Valli’ , Brisotto Giulia , Miolo Gianmaria , Canzonieri Vincenzo , Aprile Giuseppe , Corvaja Carla , Buriolla Silvia , Garattini Enrico , Puglisi Fabio 

TITLE=The potential of retinoic acid receptors as prognostic biomarkers and therapeutic targets in gastric cancer

JOURNAL=Frontiers in Oncology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1453934

DOI=10.3389/fonc.2024.1453934

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><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 <italic>Retinoic</italic>-<italic>Acid</italic>-<italic>Receptors</italic> (<italic>RARα</italic>/<italic>RARβ</italic>/<italic>RARγ</italic>/<italic>RXRα</italic>/<italic>RXRβ</italic>/<italic>RXRγ</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 <italic>Retinoic</italic>-<italic>Acid</italic>-<italic>Receptors</italic> in gastric cancer.</p></sec><sec><title>Methods</title><p>In this single institution and retrospective <italic>RAR-GASTRIC</italic> study, we consider 55 consecutive gastric cancer patients. We extract total RNA from the pathological specimens and we perform a <italic>NanoString Assay</italic> using a customized panel of genes. This allows us to determine the expression levels of the <italic>RAR</italic> and <italic>RXR</italic> mRNAs as well as other transcripts of interest.</p></sec><sec><title>Results</title><p>Our data demonstrate ubiquitous expression of the <italic>RAR</italic> and <italic>RXR</italic> mRNAs in gastric cancers. High levels of <italic>RARα</italic>, <italic>RARβ</italic>, <italic>RXRα</italic> and <italic>RXRβ</italic> show a significant association with stage IV tumors, “<italic>de novo</italic>” metastatic disease, microsatellite-stable-status, epithelial-to-mesenchymal-transition, as well as <italic>PIK3CA</italic> and <italic>TP53</italic> expression. Finally, we observe a worse <italic>overall</italic>-<italic>survival</italic> in gastric cancer patients characterized by high <italic>RARα</italic>/<italic>RARβ</italic>/<italic>RARγ</italic>/<italic>RXRβ</italic> mRNA levels.</p></sec><sec><title>Conclusions</title><p>In gastric cancer, high expression levels of <italic>RARα</italic>/<italic>RARβ</italic>/<italic>RARγ</italic>/<italic>RXRβ</italic> transcripts are associated with poor clinical and molecular characteristics as well as with reduced <italic>overall</italic>-<italic>survival</italic>. Our data are consistent with the idea that <italic>RARα</italic>, <italic>RARβ</italic>, <italic>RARγ</italic> and <italic>RXRβ</italic> represent potential prognostic markers and therapeutic targets of gastric cancer.</p></sec>