As of 2020, gastric cancer (GC) is fatal disease worldwide, with more than 1,000,000 new cases in 2020, and its mortality rate is the fourth leading cause of cancer-associated death, which is not optimistic (Sung et al., 2021). In East Asia, such as Korea and Japan, the morbidity of gastric cancer is significantly higher than other regions, but their early screening and diagnosis strategies have significantly reduced the mortality of GC patients (Hamashima et al., 2013, Kim et al., 2018). With the progress of genomics, the exploration of molecular characteristics and biomarkers of GC may be an important direction for the future treatment progress. Genomic analysis done by The Cancer Genome Atlas (TCGA) research network suggested four different molecular subtypes of GC, of which two subtypes, MSI and EBV+ , have shown promising results in terms of prognosis and treatment response (Kohlruss et al., 2019, Pietrantonio et al., 2019). But the current clinical decision is not based on molecular subtypes, and only HER2 is routinely tested as a biomarker (Smyth et al., 2020). These studies at the molecular level have enhanced our comprehension of GC biology and provided a reference for the prognosis and treatment options of GC patients. At present, there is still lacking more molecular biomarkers with high sensitivity and specificity for GC, and conventional tumor markers are not effective enough in practical application. Therefore, it is very necessary to find a reliable and effective new target and construct a prognostic model to improve the therapeutic effect and provide prognostic reference for patients with GC.

The aldolase family is the fourth enzyme involved in glycolysis and contains ALDOA, ALDOB and ALDOC, which are expressed in different human organs (Prentki and Madiraju, 2008). Recent studies have demonstrated that the abnormal expression and translocation of aldolase family members promoted tumor progression and related signal transduction. In addition, other studies have suggested that ALDOC was overexpressed and mutated in multiple cancers by gene sequencing, which might be closely related to oncogenesis. For instance, ALDOC may promote tumorigenesis in brain and kidney (Chen et al., 2014, Sáez and Slebe, 2000), but mutation of ALDOC inhibited cancer cell invasion and metastasis in oral squamous cell carcinoma (Li et al., 2016). In non-small cell lung cancer, the elevated expression level of ALDOC leads to the disassembly of β-Catenin destruction complex, reduces β-Catenin hydrolysis, and increases the cytoplasmic accumulation of β-Catenin, thereby activating the expression of multiple oncogenes and promoting cancer cell proliferation, invasion and metastasis (Yuan et al., 2021). Similarly, in breast cancer, BCDIN3D regulates ALDOC expression via let-7 microRNA, and the overexpression of ALDOC is closely associated with poor prognosis of breast cancer (Reinsborough et al., 2021). Although the role of ALDOC in metabolic pathways has been well established, it also interacts with a variety of non-metabolic proteins, such as cytoskeletal proteins and tubulin, which is essential for cancer cell proliferation through pathways other than glycolysis (Ritterson Lew and Tolan, 2012, Wang et al., 1996). Nevertheless, the effect of ALDOC on the biological behavior of GC cells has not been found.

Lymph node metastasis is the most common route of metastasis and one of the most important prognostic factors in GC patients (Okholm et al., 2014). In addition, the degree of lymphocyte infiltration can predict the prognosis of cancer patients. One research has confirmed that ALDOC is significantly correlated with the infiltration level of immune cells in intestinal tumors. Under hypoxia, immune cells will be recruited to the tumor microenvironment and induce the production of cytokines and other substances, thereby affecting the invasion and migration of tumor cells (Zhang et al., 2021a). Similarly, ALDOC promotes the growth of tumor cells by inducing the differentiation of tumor-associated macrophages(TAM) into M2 macrophages by regulating cytokines IL-10 and TGF-β (Hao et al., 2012). These results suggest that ALDOC may affect tumor lymph node metastasis by regulating the level of tumor immune infiltration. Therefore, we considered that ALDOC might play an important role in the regulation of lymph node metastasis in gastric cancer, but the role of ALDOC between lymph node metastasis and immune infiltration needs to be explored.

MicroRNAs are a group of endogenous short non-coding RNAs which play a significant role in oncogenesis. In the immune microenvironment of GC, some miRNAs have been confirmed to regulate the immune microenvironment by recruiting lymphocytes and myeloid cells and significantly change the sensitivity of GC cells to anticancer drugs (Zhang et al., 2021b). Most studies about the immune microenvironment focus on cancer cells, immune cells, cytokines and other substances. Nevertheless, miRNAs play an important role in bidirectional infiltration between tumor cells and stromal cells in the immune microenvironment, which is one of the key factors in cancer progression (Kohlhapp et al., 2015, Wang et al., 2019). Previous studies have suggested that miR-19a-5p plays important regulatory roles in lung cancer and breast cancer, but its role and potential significance in GC remain unclear (Lin et al., 2020, Yang et al., 2020).

In this study, we investigated the expression of ALDOC in GC, and analyzed the effects of ALDOC on cell proliferation, migration, immune infiltration and prognosis of GC patients. This study revealed that miR-19a-5p regulates ALDOC expression through transcription factors and constructed a prognostic model to provide a new target and reference for the treatment and prognosis analysis of GC patients.