Gastric cancer is one of the most common tumour of gastroenteric tumor in the world. China is the high incidence areas of gastric cancer, which could influence the lifetime of human[15, 16]. The advanced histological stage or distant metastasis could cause the poor prognosis of gastric cancer. Therefore, early diagnosis or surgery is significantly important to the treatment of tumor. In those studies, many scholar explored the novel biomarkers for early diagnosis or evaluation the prognosis and recurrence in gastric cancer [17–19]. TFAP-2β constituted promoter activity in gastric cancer and contributed to the development of the metabolic syndrome. TFAP-2β may influence the occurrence and development of gastric through regulating the expression of various adipokines and lipoprotein metabolism[14, 20]. Li et al reported that high VCAN was expressed in gastric cancer and considered it as a independent molecular marker for diagnosis and prognosis of gastric cancer[21].
ASPN,a member of small leucine-rich repeat proteoglycan (SLRP) family of proteins, is localized on chromosome 9q22.31 and encodes a secretory protein containing 380 amino acids[7]. It could focus on the diverse biological responses and disease conditions. In previous studies, many authors suggested that ASPN was significantly associated with the development of various types of cancer [7, 10, 22]. For example, Bàrbara et al [9] showed that ASPN and GJB2 could take part in the mechanism of local invasion in breast carcinomas. Maris et al [23] also reporetd that asporin, as a stroma-derived inhibitor of TGF-β1, could suppress the development of tumors and reduce the aggressive of breast cancer in clinical results. Besiedes, cancer-associated fibroblasts or cancer cells could secreted ASPN to regulate the epithelial to mesenchymal transition or interact with cell-membrane receptor, which could promote the invasion and migration of tumor[7]. Satoyoshi et al[24] showed that asporin could activate coordinated invasion of cancer-associated fibroblasts and scirrhous gastric cancer and promote the progression disease of tumour cells. The expression of asporin could bring a novel therapeutic molecular target for the diagnosis and treatment of gastric cancer. However, there was no reported to identify the realtionship between ASPN and clinical evaluation in gastric cancer.
In this study, we found that there was significantly different in ASPN expression between gastric cancer and normal tissue (P < 0.001). The expression of ASPN was markedly higher in gastric cancer compared with normal tissues. The result was similar with previous studies. The bioinformatic analysis also showed that increased ASPN expression in gastric cancer compared with adjacent normal gastric according to the high throughput RNA-sequencing data[5, 12]. Ding et al[8] reported that ASPN was overexpressed in gastric carcinoma tissues when compared to the corresponding noncancerous tissues. We summarized that the expression of ASPN in gastric cancer was significantly associated with clinical stage (P < 0.001) histological stage (P < 0.001) and T classification (P < 0.001), which indicated that ASPN may regulate the above clincial factors. In Jiang et al study, overall survival and diease free survival in KaplanMeier curves showed that high expression of ASPN caused the poor prognosis in GC patients (P < 0.05) [5].
Besides, logistic regression showed that ASPN expression was remarkable associated with stage classification (stage II vs stage I, OR = 3.656, P < 0.001 and stage III vs stage I, OR = 2.313, P < 0.0141) and T classification (T classification T2 vs T1, OR = 13.304, P = 0.014; T3 vs T1, OR = 20.769, P = 0.003 and T4 vs T1, OR = 24.857, P = 0.002). Those results showed that ASPN could promote the stage classification and Lymph nodes metastasis. Therefore, we hypothesized that ASPN could be potential therapeutic targets in the molecular mechanism for treatment of GC. The univariate analysis showed that increase exprssion of ASPN was remarkably associated with poor overall survival (OR:1.005, 95% CI:1.000-1.009 and P = 0.036). The multivariate Cox analysis indicated that high VCAN expression was significantly associated overall survival (HR:1.010, 95%CI: 1.005–1.015, P = 0.000), age (HR: 1.046, 95%CI: 1.024–1.068, P = 0.002) and gender (HR: 1.623, 95%CI: 1.057–2.492, P = 0.026). In previous study, the author considered ASPN as an important molecular gene in the developmeng of cancer to contribute the progression and metastasis via the epidermal growth factor receptor (EGFR) signalling pathway[8]. ASPN promotes the proliferation of GC cells by interacting with PSMD2, and knockdown of ASPN significantly increased the expression of dual specificity phosphatase 7(DUSP7), which served as a potential therapeutic target in gastric cancer [7].
We performed the high and low ASPN expression datasets by GSEA in the enrichment of the MSigDB collection (c2.cp.kegg.v6.2.symbols.gmt). We reported that GSEA showed that Pentose phosphate pathway, Base excision repair, Peroxisome, Protesome, Nucleotide excision repair, and Mismatch repair were differentially enriched in ASPN high expression phenotype in gastric cancer (FDR < 0.05, NOM p-val < 0.05). Those results was concordant with previous studies[25]. In gastric cancer, there were DNA repair systems of cancer cells could maintain the integrity and stability of the genome including base excision repair, mismatch repair,nucleotide excision repair and double strand break repair[26]. Pentose phosphate pathway play an important part in cellular metabolism, ribonucleotide and lipid biosynthesis to promote the survival of cancer cells, which sustain antioxidant responses to support cell survival and proliferation[27]. Besides, it was conducted to maintain cancer cells in anabolic demands and redox homeostasis, and cancer cells acquired multiple mechanisms to deregulate the oxidative and nonoxidative pentose phosphate pathway[28, 29]. Choi et al[30] reported that expression of pentose phosphate pathway was higher in breast cancer compared with normal tissue according to molecular subtype. Pentose phosphate pathway was significantly expressed in gastric cancer tissue with low expression of Rev-erbα, which resulted in the progession of gastric cancer[31]. Base excision repair, the most prevalent pathway in damaged bases modification, could repair the vast majority of endogenous DNA damage including alkylations, oxidations, deaminations and depurinations, as well as single-strand breaks in cancer cells[32]. Biological function of BER removed these frequently produced lesions, maintained genomic integrity and affected the clinical prognosis and overall survival of gastric cancer according to the promotion of DNA repair capacity[33]. In previous study, the aurthor could regulate the base excision repair system to inhibite the growth of gastric cancer and provide the novel perspectives to evluate gastric cancer progression based on the role of base excision repair[34].
Focal adhesion, Calcium signaling pathway, Ecm receptor interaction, TGF-ß signaling pathway, Calcium Signaling pathway and Hedgehog signaling pathway. were differentially enriched in ASPN low expression phenotype in gastric cancer (FDR < 0.001, NOM p-val < 0.01). In previous study, the enrichment analysis in gastric cancer were enriched in ECM-receptor interaction, focal adhesion, metabolism of xenobiotics and drug metabolism pathways, and the result was similar with our study[5]. Cao et al[35] also analyzed that KEGG pathways of differentially expressed genes were significantly enriched in ECM-receptor interaction, protein digestion and absorption, and the focal adhesion pathways, and the genes in the modules of protein-protein interaction were mainly involved in the ECM-receptor interaction and focal adhesion pathways. The activation of hedgehog signaling pathway could promote the neoplastic transformation and the developmeng of gastric cancer by the biological function of cancer stroma interaction[36].Therefore, we could monitor Hedgehog signaling in order to evlauated the eventually developing gastric cancer. And then, Upregulation of Hedgehog signaling pathway was associated with tumor development. Hedgehog-independent activation of Patched through the action of proteases and in particular Caspase 3, splitting the C-terminal from Patched[37, 38].
In conclusion, according to the TCGA databases, we considered ASPN expression as a potential molecular marker in the diagnosis and prognostic of overall survival in gastric cancer. Furthermore, the pentose phosphate pathway, base excision repair, peroxisome, protesome, nucleotide excision repair, and mismatch repair may be the remarkable key pathway regulated by ASPN in based on the GSEA anaysis software.