Synaptophysin-like 2 expression correlates with lymph node metastasis and poor prognosis in colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. Synaptophysin-like 2 (SYPL2) is a neuroendocrine-related protein highly expressed in skeletal muscle and the tongue. The involvement of SYPL2 in CRC, including its level of expression and function, has not been evaluated. AIM: To evaluate the correlations of SYPL2 expression with lymph node metastasis (LNM) and prognosis in patients with CRC. METHODS: The levels of expression of SYPL2 in CRC and normal colorectal tissues were analyzed in multiple public and online databases. The associations between clinical variables and SYPL2 expression were evaluated statistically, and the associations between SYPL2 expression and prognosis in patients with CRC were analyzed using the Kaplan-Meier method and univariate/multivariate Cox regression analyses. SYPL2 expression was assessed in 20 paired CRC tissue and adjacent normal colorectal tissue samples obtained from Fuyang People's Hospital, and the associations between SYPL2 expression and the clinical characteristics of these patients were investigated. Correlations between the levels of expression of SYPL2 and key targeted genes were determined by Pearson's correlation analysis. The distribution of immune cells in these samples was calculated using the CIBERSORT algorithm. Gene set enrichment analysis (GSEA) was performed to evaluate the biofunction and pathways of SYPL2 in CRC. RESULTS: SYPL2 expression was significantly lower in CRC tissue samples than in normal colorectal tissue samples (P < 0.05). High SYPL2 levels in CRC tissues correlated significantly with LNM (P < 0.05) and a poorer patient prognosis, including significantly shorter overall survival (OS) [hazard ratio (HR) = 1.9, P < 0.05] and disease-free survival (HR = 1.6, P < 0.05). High SYPL2 expression was an independent risk factor for OS in both univariate (HR = 2.078, P = 0.014) and multivariate (HR = 1.754, P = 0.018) Cox regression analyses. In addition, SYPL2 expression correlated significantly with the expression of KDR (P < 0.0001, r = 0.47) and the BRAF V600E mutation (P < 0.05). Higher SYPL2 expression was associated with the enrichment of CD8 T-cells and M0 macrophages in the tumor microenvironment. GSEA revealed that SYPL2 was associated with the regulation of epithelial cell migration, vasculature development, pathways in cancer, and several vital tumor-related pathways. CONCLUSION: SYPL2 expression was lower in CRC tissue than in normal colorectal tissue. Higher SYPL2 expression in CRC was significantly associated with LNM and poorer survival.

High expression of oncogene cadherin-6 correlates with tumor progression and a poor prognosis in gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common and fatal cancers worldwide. Effective biomarkers to aid the early diagnosis of GC, as well as predict the course of disease, are urgently needed. Hence, we explored the role and function of cadherin-6 (CDH6) in the diagnosis and prognosis of gastric cancer. METHODS: The expression levels of CDH6 in cancerous and normal gastric tissue were analyzed using multiple public databases. Gene set enrichment analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) dataset. The diagnostic efficiency of CDH6 expression in GC patients was determined through receiver operating characteristic (ROC) curve analysis. The associations between clinical variables and CDH6 expression were evaluated statistically, and the prognostic factors for overall survival were analyzed by univariate and multivariate Cox regression. 44 GC tissue samples, 20 donor-matched adjacent normal tissue samples, and associated detailed clinical information, were collected from the Tianjin Medical University General Hospital. CDH6 expression levels were determined for further validation. RESULTS: CDH6 was upregulated in GC samples compared to normal gastric tissue. Furthermore, GSEA identified the tricarboxylic acid (TCA) cycle, extracellular matrix (ECM) receptor interaction, glyoxylate and dicarboxylate metabolism, oxidative phosphorylation, and the pentose phosphate pathway as differentially enriched in GC tissue samples. According to the area under the ROC curve (AUC) values (AUC = 0.829 in the TCGA and 0.966 in the GSE54129 dataset), CDH6 expression was associated with high diagnostic efficacy. Patients with high CDH6 levels in their GC tissues had a higher T number (according to the TNM classification) and a worse prognosis than those with low CDH6 expression. Univariate and multivariate Cox regression analysis showed that CDH6 was an independent risk factor for overall survival (univariate: HR = 1.305, P = 0.002, multivariate: HR = 1.481, P < 0.001). CONCLUSION: CDH6 was upregulated in GC, and high CDH6 expression was indicative of a higher T number and a worse prognosis. Therefore, CDH6 represents a potentially independent molecular biomarker for the diagnostic and prognostic prediction of GC.

Construction and Validation of a Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Gastric Cancer.

BACKGROUND: Increasing evidence indicated that the tumor microenvironment (TME) plays a critical role in tumor progression. This study aimed to identify and evaluate mRNA signature involved in lymph node metastasis (LNM) in TME for gastric cancer (GC). METHODS: Gene expression and clinical data were downloaded from The Cancer Genome Atlas (TCGA). The ESTIMATE algorithm was used to evaluate the TME of GC. The heatmap and Venn plots were applied for visualizing and screening out intersect differentially expressed genes (DEGs) involved in LNM in TME. Functional enrichment analysis, gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network were also conducted. Furthermore, binary logistic regression analysis were employed to develop a 4-mRNAs signature for the LNM prediction. ROC curves were applied to validate the LNM predictive ability of the riskscore. Nomogram was constructed and calibration curve was plotted to verify the predictive power of nomogram. RESULTS: A total of 88 LNM related DEGs were identified. Functional enrichment analysis and GSEA implied that those genes were associated with some biological processes, such as ion transportation, lipid metabolism and thiolester hydrolase activity. After univariate and multivariate logistic regression analysis, 4 mRNAs (RASSF2, MS4A2, ANKRD33B and ADH1B) were eventually screened out to develop a predictive model. ROC curves manifested the good performance of the 4-mRNAs signature. The proportion of patients with LNM in high-risk group was significantly higher than that in low-risk group. The C-index of nomogram from training and test cohorts were 0.865 and 0.765, and the nomogram was well calibrated. CONCLUSIONS: In general, we identified a 4-mRNAs signature that effectively predicted LNM in GC patients. Moreover, the 4-mRNAs signature and nomogram provide a guidance for the preoperative evaluation and postoperative treatment of GC patients.

High expression of regulator of G-protein signalling 1 is associated with the poor differentiation and prognosis of gastric cancer.

Emerging evidence has highlighted that immune and stromal cells form the majority of the tumour microenvironment (TME), which plays important roles in tumour progression. The present study aimed to screen vital prognostic genes associated with the TME in gastric cancer (GC). The ESTIMATE algorithm was applied to calculate TME-related scores, and the relationship between clinicopathological variables and these scores was analysed. Heatmaps and Venn plots were then used to visualize and screen differentially expressed genes. Furthermore, functional enrichment analysis was performed, and a protein-protein interaction network was constructed. Kaplan-Meier curves were generated to evaluate survival differences for each hub gene. Reverse transcription quantitative PCR was employed to evaluate the expression of the three hub genes in the validation cohort. The association between gene expression, clinicopathological variables and survival was also evaluated. Higher stromal scores were associated with worse outcomes in patients with GC. In addition, higher scores were significantly associated with a higher tumour grade, American Joint Committee on Cancer stage and T stage with regard to immune scores, stromal scores and ESTIMATE scores, respectively. In total, 644 upregulated intersecting genes and 126 downregulated genes were identified. Moreover, 71 TME-associated hub genes were identified. Batch survival analysis revealed that higher expression of CXCR4, PTGFR and RGS1 was significantly associated with worse outcome. Subsequently, the relationship between high expression of RGS1 and poor prognosis was verified, and high expression of RGS1 was associated with poor differentiation. In conclusion, it was found that compared with immune cells, stromal cells may play a more important role in the prognosis of patients with GC. In addition, the influence of RGS1 expression on survival in GC patients was identified and verified, and high expression of RGS1 was found to be associated with a low differentiation degree of GC.

Novel Prognostic Nomogram for Recurrence-Free Survival of Patients With Primary Gastrointestinal Stromal Tumors After Surgical Resection: Combination of Prognostic Nutritional Index and Basic Variables.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common type of mesenchymal tumors in the digestive tract, often recrudescing even after R0 resection. Adjuvant tyrosine kinase inhibitor therapy prolonged recurrence-free survival (RFS). This study aimed to develop a novel nomogram for predicting the RFS of patients following surgical resection of GISTs. METHODS: Clinicopathologic data of patients with GISTs at Tianjin Medical University General Hospital (Tianjin, China) from January 2000 to October 2019 were retrospectively reviewed. Univariate and multivariate Cox regression analyses were used to select the suitable variables from the training cohort to construct a nomogram for 2- and 5-year RFS. The 1,000 bootstrap samples and calibration curves were used to validate the discrimination of the nomogram. The receiver operating characteristic analysis(ROC) was used to compare the predictive ability of the nomogram and present four commonly used risk stratification systems: National Institutes of Health (NIH)-Fletcher staging system; NIH-Miettinen criteria; Modified NIH criteria; and Air Forces Institute of Pathology risk criteria (AFIP). RESULTS: Univariate and multivariate analyses showed that the tumor site, tumor size, mitotic index, tumor rupture, and prognostic nutritional index were significant factors associated with RFS. These variables were selected to create the nomogram for 2- and 5-year RFS (all P<0.05). The 2- and 5-year the ROC of the nomogram were 0.821 (95% confidence interval [CI]: 0.740-0.903) and 0.798 (95% CI: 0.739-0.903); NIH-Fletcher criteria were 0.757 (95% CI: 0.667-0.846) and 0.683 (95% CI: 0.613-0.753); NIH-Miettinen criteria were 0.762 (95% CI: 0.678-0.845) and 0.718 (95% CI: 0.653-0.783); Modified NIH criteria were 0.750 (95% CI: 0.661-0.838) and 0.689 (95% CI: 0.619-0.760); and AFIP were 0.777 (95% CI: 0.685-0.869) and 0.708 (95% CI: 0.636-0.780). Hence, the predictive probabilities of our nomogram are better than those of other GIST risk stratification systems. CONCLUSION: This nomogram, combining tumor site, tumor size, mitotic index, tumor rupture, and prognostic nutritional index, may assist physicians in providing individualized treatment and surveillance protocols for patients with GISTs following surgical resection.

In situ cardiac regeneration by using neuropeptide substance P and IGF-1C peptide eluting heart patches.

Cardiovascular diseases cause huge socio-economic burden worldwide. Although a mammalian myocardium has its own limited healing capability, scaffold materials capable of releasing stem cell recruiting/engrafting factors may facilitate the regeneration of the infarcted myocardium. The aim of this research was to develop cardiac patches capable of simultaneously eluting substance P (SP) and insulin-like growth factor-1C (IGF-1C) peptide. Polycaprolactone/collagen type 1-based patches with or without SP and IGF-1C peptide were fabricated by co-electrospinning, which exhibited nanofibrous morphology. SP and IGF-1C/SP patches recruited significantly higher numbers of bone marrow-mesenchymal stem cells than that of the negative control and patch-only groups in vitro. The developed patches were transplanted in an infarcted myocardium for up to 14 days. Mice underwent left anterior descending artery ligation and received one of the following treatments: (i) sham, (ii) saline, (iii) patch-only, (iv) IGF-1C patch, (v) SP patch and (vi) IGF-1C/SP patch. SP and IGF-1C/SP patch-treated groups exhibited better heart function and attenuated adverse cardiac remodeling than that of the saline, patch-only and individual peptide containing cardiac patches. SP patch and IGF-1C/SP patch-treated groups also showed higher numbers of CD31-positive vessels and isolectin B4-positive capillaries than that of other groups. IGF-1C/SP-treated group also showed thicker left ventricular wall in comparison to the saline and patch-only groups. Moreover, IGF-1C/SP patches recruited significantly higher numbers of CD29-positive cells and showed less numbers of Tunel-positive cells compared with the other groups. These data suggest that SP and IGF-1C peptides may act synergistically for in situ tissue repair.