Gastric cancer is a common upper gastrointestinal cancer (1). It often occurs among the middle-aged and elderly and is not common in young people (under the age of 45), who represent no more than 10% of patients suffering from the disease (2). With improvements in treatment technology, the five-year survival rate of early gastric cancer can reach more than 95%, but the symptoms of gastric cancer are rare and nonspecific in the early stages of the disease (3). This multifactorial disease is associated with environmental and genetic factors and is usually diagnosed in its late stages, with a median survival period of less than 12 months (4, 5). Data show that the prognosis of patients is related to the tumor stage (6). Therefore, more and more attention has been paid to clinical staging in recent years. Obtaining accurate, reliable clinical staging is a challenging but crucial problem.

The Union for international cancer control (UICC) and the American Joint Committee on cancer (AJCC) maintain the TNM cancer control staging system, a tool used by physicians to stage different types of cancer (T), existence in the lymph nodes (N), and metastasis (M). At present, the TNM staging system is used to evaluate most malignant tumors worldwide, including gastric cancer (7). The accurate staging of gastric cancer is a crucial part of patient management, as tumor staging is the most important predictor of survival at the initial diagnosis. In addition, the treatment scheme for the tumor will vary according to different disease stages (8). Tumor prognosis prediction and treatment recommendations for gastric cancer are mainly guided by the TNM staging system (9). Preventable factors that play a role in gastric cancer development are also important. This study aimed to find biomarkers that may be involved in the progression and staging of gastric cancer to stratify patients and better target treatment.

Like other solid tumors, gastric cancer comprises several molecular subtypes with diverse biological characteristics. The increasing understanding of molecular pathways provides a basis for innovative therapies (10). Molecular targeted therapy can be used to identify specific oncogenic targets of tumor cells, killing tumor cells (11). In addition, the therapy has been shown to regulate the immune response, as some molecularly targeted drugs can increase tumor antigen expression and promote the antigen presentation of antigen-presenting cells to induce a more robust antitumor immune response (12). The expression of mRNA, a transient intermediate between genes and proteins, has shown therapeutic potential in various applications, including viral vaccines, protein replacement therapy, cancer immunotherapy, cell reprogramming, and genome editing (13). Therefore, mRNA has become a new therapeutic agent for preventing and treating various diseases (14). Using dynamic trend analysis, differential analysis, and predictive analysis, this study screened 10 genes with prognostic significance in gastric cancer (RXRG, AGT, BCHE, UBE2QL1, PLCXD3, ADCYAP1R1, NRCAM, MAMDC2, CDH19, and GAMT). Expression analysis and stage expression analysis also showed that they had high or low expression in gastric cancer and changed dynamically with the evolution of the gastric cancer stage.

The immune microenvironment plays an essential role in the development of digestive system cancer. Tumor infiltrating immune cells play a crucial role in suppressing or supporting tumor growth and development and can be effectively targeted by drugs, associated with patient survival time (15). Other studies have shown that macrophages induce PD-L1 expression and help gastric cancer cells escape cytotoxic T cell death. In addition, they can promote the proliferation of gastric cancer cells by regulating the expression of PD-L1 (16).

Moreover, macrophage infiltration is significantly correlated with the prognosis of patients with gastric cancer (17). ADCYAP1R1 has anti-inflammatory, neuroprotective and regenerative properties, and its expression may also be influenced by immune/inflammatory stimuli (18). It has been shown that deletion of ADCYAP1R1 in naïve mice results in the absence of retinal ganglion neurons and their dendrites, while increased axonal pathology and secondary increases in microglia/macrophages are also evident in the optic nerve (19). CDH19 is thought to be a member of calmodulin and establishes and maintains intercellular junctions (20). Some studies have shown that CDH19 may be a potential candidate as an immunotherapeutic target for breast cancer patients (21). MAMDC2 is a proteoglycan of completely unknown function, containing five MAM structural domains. They mediate interactions and stability and can act as an adhesion structural domain for surface receptors (22). Some studies have also shown that MAMDC2 plays a key role in the development of invasive ductal carcinoma of the breast (23). Although no clear studies have shown their direct role with immune cells in tumors, they also show that they play an important role in tumors. We found that the expression levels of BCHE, MAMDC2 and PLCXD3 were moderately positively correlated with the degree of macrophage infiltration while the expression levels of AGT, GAMT, CDH19, ADCYAP1R1, RXRG and UBE2QL1 were weakly positively correlated with the degree of macrophage infiltration. These results show that these genes can potentially regulate the recruitment and activation of immune cells in gastric cancer.

This study found that AGT is highly expressed in gastric cancer and up-regulated with the increase of the stage. This continuous high expression may also be related to the poor prognosis of patients. The results based on sample sequencing also show that the expression of AGT was up-regulated in gastric cancer as compared with the standard group. AGT is an inactive precursor of potent vasoactivity and the salt-retention hormone angiotensin II, and an elevated level of it is the primary precursor in the pathogenesis of hypertension (24, 25). AGT also plays a critical role in tumors. Oncogenic effects of high glucose on breast cancer cell growth and metastasis (26). Studies have shown that AGT can also inhibit the invasion and migration of colorectal cancer (27). In this study, we performed a WGCNA of the sequenced expression matrix, which revealed that AGT was located in the antiquewhite1 module, closely related to gastric cancer. Based on the genes of this module, we explored the genes that have a coexpression relationship with AGT. The analysis shows that BRD9, GOLPH3, NOM1, KLHL25, and PSMD11 interact with AGT.

In conclusion, the expression of AGT is up-regulated in gastric cancer and the gastric cancer stages, and its continuous up-regulation is closely related to the poor prognosis of patients with gastric cancer. It is suggested that AGT may contribute to gastric cancer progression and could be used as a potential biomarker or therapeutic target in gastric cancer. However, there are deficiencies in this study, and in vitro experiments are needed to determine the critical signal pathways related to AGT.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

This study was supported by the key discipline “minimally invasive oncology of acupuncture and Moxibustion” (2017-XK-A12) of Zhejiang Administration of traditional Chinese medicine and the inheritance studio of Pangde Xiang famous old traditional Chinese medicine experts (2A12012014).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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