Background
Gastric cancer is one of the most well-known cancers of the gastrointestinal tract. In China, it is ranked third as far as incidence rate is concerned and is a major cause of cancer mortality [
1]. Systematic treatment regimens are being considerably improved in clinical practice; however, the prognosis of gastric cancer still remains unfavourable because of poor recognition and suboptimal risk stratification of the preneoplastic condition, atrophic gastritis, and aggressive cancer behaviour [
2,
3]. Lauren’s classification is the most useful and widely applicable classification for pathology, generally dividing the disease into intestinal-, diffuse-, and mixed-subtype [
4]. Although a few of molecular biomarkers have been used for predicting prognosis to date [
5,
6], few of clinical and prognostic biomarkers are available in gastric cancer. Therefore, searching biomarkers for prognosis prediction in gastric cancer patients could be helpful in deciding more effective clinical regimen.
The deregulation of metabolic pathways fuels cell metastasis during tumorigenesis, possibly contributing to the poor prognosis in gastric cancer. Phosphoserine phosphatase (PSPH) is an enzyme, which is involved in the process of L-serine biosynthesis. Recent studies indicated that PSPH mainly plays role in multiple aspects of cell behaviours such as proliferation and differentiation by producing precursors for the biosynthesis of diverse compounds including neurotransmitters, glycolipids and thymidine [
7,
8]. Additionally, several studies reported that augmented PSPH level is correlated with the prognosis in multiple cancers including cutaneous squamous cell carcinoma [
9], breast cancer [
10], non-small cell lung cancer [
11], colorectal cancer [
12] and hepatocellular carcinoma [
13]. This indicates that PSPH may serve as a biomarker for prognosis in cancers. However, very little is known about the prognostic role of PSPH in patients with gastric cancer.
In this study, we analysed PSPH expression across multiple cancers using Pan-Cancer data and focused on the relationship between PSPH expression and gastric cancer. We further demonstrated the differential expression of PSPH in the intestinal- and diffuse-type gastric cancer through immunohistochemistry. Moreover, we observed that patients with high expression of PSPH had inferior survival because of low infiltration of immune cells. In summary, PSPH may help to predict prognosis in patients with gastric cancer and is associated with immune cells.
Discussion
It was observed in the study that PSPH expression was higher in patients with gastric cancer than in normal individuals. Patients with high expression of PSPH had poor survival. More importantly, high expression of PSPH was found to be significantly associated with the low score of immune cells, mainly activated memory CD4 T cells, which conferred poor survival. These results indicated that differential expression of PSPH may contribute to survival of patients with gastric cancer. Furthermore, we speculated that the underlying mechanism of action was due to the dysregulation of PSPH–immune axis, which might provide a new treatment regimen for patients with gastric cancer.
PSPH is associated with the development of various cancers and is a promising prognostic biomarker in different cancers such as advanced colorectal cancer [
17], thyroid cancer [
18] and melanoma [
19]. Similarly, we found high PSPH expression in most of the patients with gastric cancer who had a dismal survival. These findings indicated that differential expression of PSPH could play an important role in the carcinogenesis of gastric cancer. Recently, Kim et al. have reported that specific subtypes of gastric cancer are characterised by differential sensitivity to immunotherapy such as PD-L1 blockade [
20], and may also display different levels of PSPH expression across pathological subtypes. Autophagy phenomena is highly associated with PSPH expression in cancers [
21], implicating that PSPH expression is important in gastric cell physiology and the interaction with Helicobacter, as evident from genetic polymorphisms in the population that predispose to the disease [
22]. Apart from these mechanisms, it have been reported in many previous studies that the action PSPH in cancers are 5-fluorouracil-induced increased accumulation of reactive oxygen species through PSPH-mediated serine synthesis in colorectal cancer [
23], inhibition of apoptosis in hepatocellular cancer, promotion of osteoclastogenesis in bone metastatic breast cancer [
24] and notably, EGFR amplification in lung adenocarcinoma which was associated with PSPH overexpression [
25].
Recent studies reported that alteration of tumour immune microenvironment in gastric cancer is a pivotal strategy for predicting the immunotherapeutic responses and prognosis, which might provide new treatment strategies for patients [
26,
27]. To explore the possible mechanism of PSPH affecting the survival, we analysed the relationship between PSPH expression and ESTIMATE, stromal and immune scores and found that the patients with higher PSPH expression conversely exhibited a lower ESTIMATE, stromal and immune scores. In particular, patients with lower immune score had a poor prognosis. Furthermore, through the Cibersort algorithm, we found that the amount of resting NK cells, activated memory CD4 T cells and M0 macrophages was high in high PSPH expression group, whereas that of memory B cells and activated or resting mast cells was low. It confirmed that PSPH may participate in the regulation of the tumour immune microenvironment in gastric cancer.
The tumour immune microenvironment contains multiple complex components capable of suppressing and promoting tumour metastasis and growth [
28]. Substantial evidence has already indicated that cellular metabolism is involved in immune cell functions. PSPH-mediated serine synthesis is a well-known process associated with various cellular responses. It is upregulated in cancer cells as a mechanism contributing to enhanced nucleotide and amino acid synthesis with regard to cell proliferation and antioxidant production, and it is a potential novel therapeutic target for treating cancers [
29‐
31]. T cells and macrophages are the most abundant cells among all types of immune cells with varying functions. Noga et al. reported that serine biosynthesis is necessary for T cell expansion in acquired immune responses [
32]. On the other hand, in certain animal models, excessive serine management can suppress inflammatory responses by increasing glutathione synthesis [
33]. Recent experimental studies have shown that macrophages promote the cancer progression by releasing various cytokines, including chemokines and inflammatory factors [
34], namely grouped into M1 and M2. However, these two sub-types have opposite effects on tumour progression. M2 macrophages are mainly conducive for angiogenesis and stimulate tumour cell metastasis [
35]; by the contrast, M1 macrophages are the tumour suppressors as per the effects of pro-inflammatory and cytotoxic cell expression. Along with the upregulation of PSPH, the contents of M0 macrophages, resting NK cells and activated memory CD4 T cells also increased. Wu et al. have recently reported that patients with gastric cancer with high expression of ADAMTS12 had an unfavourable prognosis, and interestingly, the content of M0 macrophages was also increased [
36]. In another study, it was demonstrated that high-risk in patients with lung cancer was associated with significantly high levels of activated memory CD4 T cells, resting NK cells and M0 macrophages [
37]. Through data analysis, we found that patients with gastric cancer with high expression of PSPH and low immune score had poor prognosis because of a high amount of M0 macrophages and a low amount of M1 macrophages, which was consistent with the previous study [
38]. Collectively, this study demonstrated that the metabolic gene PSPH could affect the density of immune cells in patients with gastric cancer, and it could be an important clue for deciding treatment regimens.
Moreover, this study revealed that the mechanism of action of PSPH as an indicator of poor outcome in gastric cancer was associated with immune cell infiltrations. This indicated that PSPH could affect the infiltration of immune cells in gastric cancer. Further studies are warranted to explore and confirm the mechanism of PSPH in inhibiting immune cells in vitro and in vivo.
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