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

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 GDF1 5, GFRAL and RET may provide significant clinical implications for the prognosis prediction of GC patients.

Growth differentiation factor 15 induces cisplatin resistance through upregulation of xCT expression and glutathione synthesis in gastric cancer

“…Recent evidence showed that tumor grading is related to GDF15 and GFRAL expression, and Lauren's classification is related to GFRAL expression in gastric cancer patients 53 . Inconsistently, we revealed that GDF15 and GFRAL protein expressions might not be good prognostic factors for patients with gastric cancer (Tables 1 and 3).…”

Integrating metabolomics and proteomics to identify novel drug targets for heart failure and atrial fibrillation

“…KPCA is targeted by HF drug midostaurin, and is involved in the significantly enriched RET signalling pathway, together with GFRA1 and RET ( Appendix Table S10 ). The RET receptor is activated by GFRA1 and is needed for GDF15 signalling 56 , where GDF15 concentrations are predictive of HF outcome 57,58 . GDF15 has also been shown to associate with stroke, bleeding, and mortality in AF patients 59 .…”

The prognostic role of p53 and its correlation with CDK9 in urothelial carcinoma

“…The expression of CDK9 was determined using IHC assays according to the protocol described in Buchholz et al study [ 16 ]. In the beginning, standardization and optimization of the IHC method were performed on a recommended tissue, based on the antibody datasheet and reference sources (The Human Protein Atlas: https://www.proteinatlas.org ; [ 17 ]).…”

“…The results from the CDK9 group have been published in our recent article and are available on request from the corresponding author; reference [ 16 ]. The data presented in this study are available on request from the corresponding author.…”