The Potential of Retinoic Acid Receptors As Prognostic Biomarkers and Therapeutic Targets in Gastric Cancer

Overview

Journal Front Oncol

Specialty Oncology

Date 2024 Sep 26

PMID 39323992

Authors

Silvio Ken Garattini

Debora Basile

Valli De Re

Giulia Brisotto

Gianmaria Miolo

Vincenzo Canzonieri

Giuseppe Aprile

Carla Corvaja

Silvia Buriolla

Enrico Garattini

Fabio Puglisi

Affiliations

Soon will be listed here.

Abstract

Background: 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 -- (/////) 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 -- in gastric cancer.

Methods: In this single institution and retrospective study, we consider 55 consecutive gastric cancer patients. We extract total RNA from the pathological specimens and we perform a using a customized panel of genes. This allows us to determine the expression levels of the and mRNAs as well as other transcripts of interest.

Results: Our data demonstrate ubiquitous expression of the and mRNAs in gastric cancers. High levels of , , and show a significant association with stage IV tumors, "" metastatic disease, microsatellite-stable-status, epithelial-to-mesenchymal-transition, as well as and expression. Finally, we observe a worse - in gastric cancer patients characterized by high /// mRNA levels.

Conclusions: In gastric cancer, high expression levels of /// transcripts are associated with poor clinical and molecular characteristics as well as with reduced -. Our data are consistent with the idea that , , and represent potential prognostic markers and therapeutic targets of gastric cancer.

References

Bang Y, Van Cutsem E, Feyereislova A, Chung H, Shen L, Sawaki A . Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376(9742):687-97. DOI: 10.1016/S0140-6736(10)61121-X. View

Lo-Coco F, Hasan S, Montesinos P, Sanz M . Biology and management of therapy-related acute promyelocytic leukemia. Curr Opin Oncol. 2013; 25(6):695-700. DOI: 10.1097/CCO.0000000000000013. View

Zhang R, Banik N, Ray S . Combination of all-trans retinoic acid and interferon-gamma upregulated p27(kip1) and down regulated CDK2 to cause cell cycle arrest leading to differentiation and apoptosis in human glioblastoma LN18 (PTEN-proficient) and U87MG (PTEN-deficient).... Cancer Chemother Pharmacol. 2007; 62(3):407-16. DOI: 10.1007/s00280-007-0619-0. View

Bolis M, Paroni G, Fratelli M, Vallerga A, Guarrera L, Zanetti A . All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells. Cancers (Basel). 2020; 12(5). PMC: 7281473. DOI: 10.3390/cancers12051169. View

Jin J, Li X, Xing L, Chang Y, Wu L, Jin Z . Addition of all-trans-retinoic acid to omeprazole and sucralfate therapy improves the prognosis of gastric dysplasia. J Int Med Res. 2015; 43(2):204-16. DOI: 10.1177/0300060514559791. View

Nguyen P, Giraud J, Chambonnier L, Dubus P, Wittkop L, Belleannee G . Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma. Clin Cancer Res. 2016; 23(6):1586-1597. DOI: 10.1158/1078-0432.CCR-15-2157. View

Puviani M, Milani M . Treatment of Grade II and III Actinic Keratosis Lesions with a Film-Forming Medical Device Containing Sunscreen/Piroxicam 0.8% and a Retinoic Acid/Glycolic Gel: A Pilot Trial. Dermatol Ther (Heidelb). 2018; 8(3):399-404. PMC: 6109025. DOI: 10.1007/s13555-018-0244-3. View

Kumar S, Dolle P, Ghyselinck N, Duester G . Endogenous retinoic acid signaling is required for maintenance and regeneration of cornea. Exp Eye Res. 2016; 154:190-195. PMC: 5363406. DOI: 10.1016/j.exer.2016.11.009. View

Derks S, Liao X, Chiaravalli A, Xu X, Camargo M, Solcia E . Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers. Oncotarget. 2016; 7(22):32925-32. PMC: 5078063. DOI: 10.18632/oncotarget.9076. View

10.

Centritto F, Paroni G, Bolis M, Garattini S, Kurosaki M, Barzago M . Cellular and molecular determinants of all-trans retinoic acid sensitivity in breast cancer: Luminal phenotype and RARα expression. EMBO Mol Med. 2015; 7(7):950-72. PMC: 4520659. DOI: 10.15252/emmm.201404670. View

11.

Lodi G, Franchini R, Warnakulasuriya S, Varoni E, Sardella A, Kerr A . Interventions for treating oral leukoplakia to prevent oral cancer. Cochrane Database Syst Rev. 2016; 7:CD001829. PMC: 6457856. DOI: 10.1002/14651858.CD001829.pub4. View

12.

Bermudez A, Arranz-Salas I, Mercado S, Lopez-Villodres J, Gonzalez V, Rius F . Her2-Positive and Microsatellite Instability Status in Gastric Cancer-Clinicopathological Implications. Diagnostics (Basel). 2021; 11(6). PMC: 8228707. DOI: 10.3390/diagnostics11060944. View

13.

Meyskens Jr F, Surwit E, MOON T, Childers J, Davis J, Dorr R . Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J Natl Cancer Inst. 1994; 86(7):539-43. DOI: 10.1093/jnci/86.7.539. View

14.

Nguyen P, Giraud J, Staedel C, Chambonnier L, Dubus P, Chevret E . All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth. Oncogene. 2016; 35(43):5619-5628. DOI: 10.1038/onc.2016.87. View

15.

Sun B, Wang Y, Sun J, Zhang C, Xia R, Xu S . Establishment of patient-derived xenograft models of adenoid cystic carcinoma to assess pre-clinical efficacy of combination therapy of a PI3K inhibitor and retinoic acid. Am J Cancer Res. 2021; 11(3):773-792. PMC: 7994170. View

16.

Marshall H, Morrison A, Studer M, Popperl H, Krumlauf R . Retinoids and Hox genes. FASEB J. 1996; 10(9):969-78. View

17.

Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo H . Alpelisib for -Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019; 380(20):1929-1940. DOI: 10.1056/NEJMoa1813904. View

18.

Garattini E, Bolis M, Garattini S, Fratelli M, Centritto F, Paroni G . Retinoids and breast cancer: from basic studies to the clinic and back again. Cancer Treat Rev. 2014; 40(6):739-49. DOI: 10.1016/j.ctrv.2014.01.001. View

19.

Cristescu R, Lee J, Nebozhyn M, Kim K, Ting J, Wong S . Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015; 21(5):449-56. DOI: 10.1038/nm.3850. View

20.

Mark M, Ghyselinck N, Chambon P . Function of retinoic acid receptors during embryonic development. Nucl Recept Signal. 2009; 7:e002. PMC: 2670431. DOI: 10.1621/nrs.07002. View