The loss of alleles in 8p11.2-12, 8p21-22 and 8p23.1 in the human chromosome 8 is reported to be a common characteristic in esophageal(13) , colorectal (14, 15) and prostate cancers (16-20). This therefore suggests that there are multiple tumor suppressor genes (TSG) on the short arm of chromosome 8. Previous studies have shown that 8p loss also occurs in GC (21, 22). The PPP1R3B gene is located on chromosome 8p23.1. However, no study exists that explores the relationship and importance of PPP1R3B in cancer patients, more so in gastric adenocarcinoma. Our study showed that the overexpression of PPP1R3B conferred a shorter survival time and higher mortality rates in GC patients. Therefore, PPP1R3B may be considered an oncogene in GC.
In this study, we analyzed the differential expression of the PPP1R3B gene in clinical variables and found that PPP1R3B was highly expressed in GC patients with tumor, thus increasing their risk of death. This was consistent with survival analysis, indicating that high expression of PPP1R3B confers a short survival time in GC patients. A comprehensive survival analysis including stratified analysis and co-analysis further investigated the clinical variables as well as the association between expression of PPP1R3B and OS in GC patients. Time-dependent ROC analysis showed that the PPP1R3B expression profile could reliably predict OS in GC patients. This finding was further verified in the KM plotter database. Therefore, PPP1R3B may be an oncogene in GC and plays a role in increased mortality in patients.
The gene is a serine/threonine kinase, regulating glycogen synthesis in the liver and skeletal muscles (23-25). It has previously been shown to be actively involved in the development of Alzheimer's disease (26), hepatic steatosis (27), and lipid levels in patients of European origin (28). Cancer is a kind of metabolic disease and metabolic disorders tend to play an integral role in the occurrence and development of the ailment (29). Hanahan et al highlighted metabolic changes as one of the ten characteristics of malignant tumors (30). A defect in lipid metabolism for instance, may affect the proliferation and differentiation of tumor cells and accelerate the occurrence and development of cancer(31). Actually, a decrease of choline and cholesterol in serum and tissues of patients with GC can be employed as a biomarker for early diagnosis of GC (32-34). This highlights the significance of defects in lipid metabolism and cell membrane biosynthesis in cancer progression.
In addition, PPP1R3B has been reported to play a role in activating glycogen synthetase (GYS) and inactivating glycogen phosphorylase resulting to abnormal metabolism of glycogen. GYS is the key enzyme and rate limiting enzyme in glycogen synthesis (35). Hypoxia inducible factor-1 (HIF-1) increases GYS levels in tumor cells, up-regulates the production of glycogen in cells and makes cells more tolerant to the hypoxia and nutritional deficiency. This suggests that glycogen synthesis caused by the expression of GYS plays a crucial role in the stressful growth environment of tumor cells (36, 37). Glycogen metabolism is an important process for energy generation in tumor cells (5, 38). Previous studies have shown glycogen accumulation to be a characteristic feature in many tumor cells and tissues (39-43). In addition, glycogen is involved in regulating the proliferation of tumor cells (44) and may therefore be an important signal molecule. High concentration of glycogen can activate AMPK, while continuous activation of AMPK can cause cell aging and inhibition of multiplication. Skwarski et al (45) reported that the risk of GC recurrence increased with prolonged operation time, which may be related to glycogen storage. Therefore, it is possible to artificially reduce the amount of glycogen and as a result inhibit the growth of cancer by maintaining the cell cycle at the G1 stop or G0 states.
The GSEA analysis indicated that PPP1R3B may be related to hypoxia, HIF1A, SOX4, T cell receptor signaling pathway, differentiation and T cell homeostasis, lipopolysaccharide mediated signaling pathway and antigen receptor mediated signaling pathway. Genome-wide co-expression analysis indicated that the PPP1R3B gene plays important roles in metabolic processes and pathways.
Studies have shown that the expression of SOX4 is higher in gastric tumor tissues compared to those with no tumors. The high expression of SOX4 in gastric tumor tissues was largely linked to tumor development and metastasis (46). T cell immunity is an important part of the human immune system and an effective T cell response is necessary for sufficient control of viral infections and growth of tumors (47). Therefore, T cell immunity plays a significant role in many cancers, including, lung (48), colorectal cancer(49), breast cancer (50) and ovarian cancer(51). CD4 + T cells and CD8 + T cells, which influence the progression and prognosis of GC, are important cell types in T-cell immunity (52, 53). Some studies have shown that beta-catenin/ T cytokine (TCF) mediated transcription (classical Wnt signaling) can lead to chromosomal instability (CIN) (54), leading to the development of GC (55). Our study suggests that the inhibition of T cell differentiation, homeostasis and signaling pathway may affect the prognosis of GC.
Despite the findings, our study has a number of limitations. First, the clinical information was only acquired from the TCGA database hence it is incomprehensive. We therefore need to study multiple databases in order to make our findings more conclusive. Secondly, in the TCGA database, the expression data for only 32 adjacent tissues was available. The insufficient sample size might therefore underrepresent the outcomes of survival analyses. Thirdly, TCGA is an open database hence the underlying molecular mechanisms through which PPP1R3B affects the occurrence and prognosis of GC needs to be further interrogated.
Although our study had a few limitations, to the best of our knowledge, it was the first one to explore the prognostic value of PPP1R3B in gastric adenocarcinoma. Comprehensive survival analysis suggests that PPP1R3B might be a potential independent prognostic determinant for the OS of GC patients. Moreover, GSEA were used to reveal the cancer-related biological processes and pathways. Once these findings are validated, we expect PPP1R3B to be used in the diagnosis and treatment for GC.