J Cancer 2021; 12(15):4698-4709. doi:10.7150/jca.55511

Research Paper

Expression of the Body-Weight Signaling Players: GDF15, GFRAL and RET and their clinical relevance in Gastric Cancer

Karolina Buchholz1,2*, Paulina Antosik1*, Dariusz Grzanka1, Maciej Gagat2, Marta Smolińska1, Alina Grzanka2, Arkadiusz Gzil1, Anna Kasperska1, Anna Klimaszewska-Wiśniewska1✉

1. Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland.
2. Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland.
*Equal contributions to this work.

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Citation:
Buchholz K, Antosik P, Grzanka D, Gagat M, Smolińska M, Grzanka A, Gzil A, Kasperska A, Klimaszewska-Wiśniewska A. Expression of the Body-Weight Signaling Players: GDF15, GFRAL and RET and their clinical relevance in Gastric Cancer. J Cancer 2021; 12(15):4698-4709. doi:10.7150/jca.55511. Available from https://www.jcancer.org/v12p4698.htm

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Abstract

The existence, the functional role and clinical relevance of GDF15 and its signaling through a GFRAL/RET-dependent complex in gastric cancer (GC) and other human tumors remain to be elucidated, despite the widespread recognition of obesity as an important cancer-predisposing factor. Therefore, we aimed to analyze the expression levels of GDF15, GFRAL and RET in GC tissues in relation to each other and clinicopathological features, including patient survival, in order to establish a potential implication of the body-weight signaling pathway in the pathology and clinical outcome of GC. Protein expression was examined by immunohistochemistry on tissue microarrays containing 104 and 30 consecutive GC and normal gastric mucosa samples, whereas gene expression data for The Cancer Genome Atlas cohort of 413 GC patients were obtained from public sources. We found that the protein expression of GDF15, GFRAL and RET was significantly elevated and positively correlated in our set of GC tissues, which was reflected in their tendency to be overexpressed in low-grade and intermediate-grade tumors rather than high-grade ones. No other relationships between the expression status of the examined proteins and clinicopathological characteristics of GC patients were found. Through in silico data analysis, we showed that high GDF15 expression was associated with better overall survival (OS) of GC patients, whereas the opposite was true for high levels of GFRAL or RET. Specifically, GFRAL and RET emerged as independent prognostic factors associated with poor OS. Furthermore, high combined expression of the three markers: GDF15+GFRAL+RET was significantly associated with reduced OS, and it was an independent prognostic factor of borderline significance in terms of OS, when adjusted for covariates. If validated in large-scale studies, the individual and combined expression of GDF15, GFRAL and RET may provide significant clinical implications for the prognosis prediction of GC patients.

Keywords: GDF15, GFRAL, RET, gastric cancer, prognostic factor