Prognostic Biomarker For Gastric Cancer Patients Research Articles

The prognostic roles of long non-coding RNA SNHG17 in the patients with gastric cancer.

Dysregulated long non-coding RNAs (lncRNAs) might exert critical roles in pathways associated with gastric cancer (GC) development. Long non-coding RNA (SNHG17), a newly identified lncRNA, has been reported to be dysregulated in several tumors. Our present study aimed to explore the expression level of SNHG17 in patients with GC and investigate the relationship between the SNHG17 level and the prognosis of GC patients. The expression levels of SNHG17 were detected by Real-time-quantitative Polymerase Chain Reaction (RT-qPCR). The chi-square test was performed to investigate the associations between SNHG17 expression and the clinical features of GC patients. The prognostic value of SNHG17 was demonstrated using Kaplan-Meier method and multivariate Cox regression analysis. We showed that SNHG17 was significantly up-regulated in GC tissues compared with adjacent normal gastric tissues (p<0.01) and higher expression of SNHG17 was observed in advanced GC tissues. The results by analyzing the clinicopathological features showed that overexpression of SNHG17 expression was associated with advanced TNM stage (p=0.006), positively lymph node metastasis (p=0.006) and positively distant metastasis p=0.024). Moreover, clinical assays revealed that patients with high SNHG17 expression levels had a significantly shorter overall survival (OS) (p=0.0034) and progression-free survival (PFS) (p=0.0002) than those expressing lower. Finally, multivariate assays showed that SNHG17 was an independent prognostic marker for both OS and PFS of patients with GC. Our findings indicated that SNHG17 was a novel molecule involved in GC progression, providing a potential prognostic biomarker for GC patients.

Prognostic implications of MYBL2 in resected Chinese gastric adenocarcinoma patients.

Background and aimGastric cancer (GC), a malignant tumor worldwide, is mostly diagnosed at an advanced stage. We selected the oncogene encoding transcription factors MYBL2 to investigate the connection between MYBL2 expression and GC prognosis.Materials and methodsMYBL2 mRNA and protein expression were measured by real-time PCR and immunohistochemistry, respectively. The relationship between MYBL2 protein expression and survival time was estimated by the Kaplan–Meier analysis. Cox proportional hazards model was used to evaluate the prognostic impact of MYBL2 expression.ResultsThe overexpression of MYBL2 was related to tumor cell differentiation, Lauren type, and metastasis of lymph nodes (P<0.05). In the MYBL2 overexpression group, the median disease free survival was even poorer (P=0.000) and it comes to median overall survival (P=0.000). The study showed that MYBL2 expression was an independent hazard for disease free survival (P=0.004).ConclusionThe results of this study suggest that MYBL2 could indicate a promisingly prognostic biomarker for GC patients.

Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer

BackgroundAdenosine-to-inosine (A-to-I) RNA editing is catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes. Recent evidence suggests that RNA editing of antizyme inhibitor 1 (AZIN1) RNA is emerging as a key epigenetic alteration underlying cancer pathogenesis.MethodsWe evaluated AZIN1 RNA editing levels, and the expression of its regulator, ADAR1, in 280 gastric tissues from 140 patients, using a RNA editing site-specific quantitative polymerase chain reaction assays. We also analyzed the clinical significance of these results as disease biomarkers in gastric cancer (GC) patients.ResultsBoth AZIN1 RNA editing levels and ADAR1 expression were significantly elevated in GC tissues compared with matched normal mucosa (P < 0.0001, 0.0008, respectively); and AZIN1 RNA editing was positively correlated with ADAR1 expression. Elevated expression of ADAR1 significantly correlated with poor overall survival (P = 0.034), while hyper-edited AZIN1 emerged as an independent prognostic factor for OS and disease-free survival in GC patients [odds ratio (OR):1.98, 95% CI 1.17–3.35, P = 0.011, OR: 4.55, 95% CI 2.12–9.78, P = 0.0001, respectively]. Increased AZIN1 RNA editing and ADAR1 over-expression were significantly correlated with key clinicopathological factors, such as advanced T stage, presence of lymph node metastasis, distant metastasis, and higher TNM stages in GC patients. Logistic regression analysis revealed that hyper-editing status of AZIN1 RNA was an independent risk factor for lymph node metastasis in GC patients [hazard ratio (HR):3.03, 95% CI 1.19–7.71, P = 0.02]. Conclusions: AZIN1 RNA editing levels may be an important prognostic biomarker in GC patients, and may serve as a key clinical decision-making tool for determining preoperative treatment strategies in GC patients.

Overexpression of CLC-3 is regulated by XRCC5 and is a poor prognostic biomarker for gastric cancer

BackgroundRecently, many potential prognostic biomarkers for gastric cancer (GC) have been identified, but the prognosis of advanced GC patients remains poor. Chloride channels are promising cancer biomarkers, and their family member chloride channel-3 (CLC-3) is involved in multiple biological behaviors. However, whether CLC-3 is a prognostic biomarker for GC patients is rarely reported. The molecular mechanisms by which CLC-3 is regulated in GC are unclear.MethodsThe expression of CLC-3 and XRCC5 in human specimens was analyzed using immunohistochemistry. The primary biological functions and pathways related to CLC-3 were enriched by RNA sequencing. A 5′-biotin-labeled DNA probe with a promoter region between − 248 and + 226 was synthesized to pull down CLC-3 promoter-binding proteins. Functional studies were detected by MTS, clone formation, wound scratch, transwell, and xenograft mice model. Mechanistic studies were investigated by streptavidin-agarose-mediated DNA pull-down, mass spectrometry, ChIP, dual-luciferase reporter assay system, Co-IP, and immunofluorescence.ResultsThe results showed that CLC-3 was overexpressed in human GC tissues and that overexpression of CLC-3 was a poor prognostic biomarker for GC patients (P = 0.012). Furthermore, higher expression of CLC-3 was correlated with deeper tumor invasion (P = 0.006) and increased lymph node metastasis (P = 0.016), and knockdown of CLC-3 inhibited cell proliferation and migration in vitro. In addition, X-ray repair cross-complementing 5 (XRCC5) was identified as a CLC-3 promoter-binding protein, and both CLC-3 (HR 1.671; 95% CI 1.012–2.758; P = 0.045) and XRCC5 (HR 1.795; 95% CI 1.076–2.994; P = 0.025) were prognostic factors of overall survival in GC patients. The in vitro and in vivo results showed that the expression and function of CLC-3 were inhibited after XRCC5 knockdown, and the inhibition effects were rescued by CLC-3 overexpression. Meanwhile, the expression and function of CLC-3 were promoted after XRCC5 overexpression, and the promotion effects were reversed by the CLC-3 knockdown. The mechanistic study revealed that knockdown of XRCC5 suppressed the binding of XRCC5 to the CLC-3 promoter and subsequent promoter activity, thus regulating CLC-3 expression at the transcriptional level by interacting with PARP1.ConclusionsOur findings indicate that overexpression of CLC-3 is regulated by XRCC5 and is a poor prognostic biomarker for gastric cancer. Double targeting CLC-3 and XRCC5 may provide the promising therapeutic potential for GC treatment.

CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1\u03b1 axis to inhibit gastric tumorigenesis

Metabolic dysfunction is a hallmark of gastric cancer (GC). In this study, we reported the identification of Calcium Binding Protein 39-Like (CAB39L) as a novel regulator of tumor metabolism in GC. CAB39L mRNA was frequently silenced by promoter methylation in GC cell lines and tissues. Functional studies suggested that CAB39L functions as a tumor suppressor, as overexpression of CAB39L elicited suppression of multiple cancer phenotypes both in GC cells and an orthotopic mouse model; whilst its knockdown promoted tumorigenesis. Mechanistically, CAB39L interacted with LKB1-STRAD complex and induced LKB1, leading to the phosphorylation and activation of AMPKα/β. LKB1-AMPK activation in GC cell lines was tumor suppressive, as metformin (an AMPK activator) inhibited GC cell growth in the CAB39L-silenced cells. Moreover, knockdown of LKB1 reversed growth inhibitory effect of CAB39L, indicating that tumor suppression by CAB39L depended on LKB1-AMPK. RNAseq and gene set enrichment analysis revealed that CAB39L was closely correlated with oxidative phosphorylation and mitochondrial biogenesis. Consistently, CAB39L-induced p-AMPK elicited PGC1α phosphorylation and increased the expression of genes involved in mitochondrial respiration complexes. Accordingly, CAB39L reversed the Warburg effect in GC, as evidenced by enhanced oxygen consumption rate and reduced extracellular acidification rate; inversely, CAB39L knockdown promoted a metabolic shift towards the Warburg phenotype. In GC patients, CAB39L promoter hypermethylation was correlated with poor prognosis. Our data demonstrate that CAB39L is a novel tumor suppressor which suppresses tumorigenesis by promoting LKB1-AMPK-PGC1α axis, thereby preventing a metabolic shift that drives carcinogenesis. CAB39L methylation is a potential prognostic biomarker for GC patients.

KCND2 upregulation might be an independent indicator of poor survival in gastric cancer.

We aimed to investigate the expression of voltage-gated potassium channels KCND1/KCND2/KCND3 in gastric cancer (GC) and normal stomach tissues and to investigate the prognostic value of the upregulated gene KCND2. A retrospective analysis was performed using data from large available databases. KCND2 was significantly upregulated at the mRNA and protein levels in GC compared with that in normal stomach tissues. High KCND2 RNA expression was independently associated with shorter overall survival (HR: 1.634, 95% CI: 1.135-2.352; p=0.008) and recurrence-free survival (HR: 2.644, 95% CI: 1.438-4.863; p=0.002). Data mining in the Kaplan-Meier plotter confirmed the prognostic value of KCND2. KCND2 upregulation is a valuable prognostic biomarker in GC patients, in terms of overall survival and recurrence-free survival.

Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis

Background/Aims: Human mutL homolog 1 (MLH1) promoter methylation was reported in gastric cancer (GC). This study determined the clinicopathological, prognostic, and diagnostic effects of MLH1 promoter methylation in GC. Methods: The combined odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence intervals (95% CI) were calculated. The pooled sensitivity, specificity, and area under the curve (AUC) were analyzed. Results: A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis. MLH1 promoter methylation was significantly higher in GC samples than in gastric adenomas, chronic gastritis, adjacent tissues, normal gastric mucosa, and normal healthy blood samples, but it exhibited a similar frequency in GC vs. intestinal metaplasia and dysplasia samples. MLH1 promoter methylation correlated with age and microsatellite instability (MSI), but it was not associated with gender, H. pylori infection, smoking, drinking behaviors, pathological histology, tumor differentiation, clinical stage, lymph node status, distant metastasis, or overall survival of GC. MLH1 promoter methylation exhibited a poor sensitivity value (< 0.5) in patients with GC compared with adjacent tissues, gastric adenomas, chronic gastritis, normal gastric mucosa, and normal healthy blood samples. The pooled sensitivity, specificity, and AUC of MLH1 promoter methylation in GC with MSI vs. GC with microsatellite stability (MSS) samples were 0.64, 0.96, and 0.90, respectively. Conclusions: Our results suggest that the detection of MLH1 promoter methylation may be a potential prognostic biomarker for GC patients with MSI.

Clinical Significance of Myeloid Zinc Finger 1 Expression in the Progression of Gastric Tumourigenesis

Background/Aims: To investigate the clinical significance of myeloid zinc finger 1 (MZF1) expression in various gastric mucosal lesions including chronic superficial gastritis (CSG), chronic atrophic gastritis (CAG), intestinal metaplasia (IM), dysplasia (DYS) and gastric cancer (GC) in comparison with normal tissues and gastric cell lines. Methods: MZF1 protein expression was detected using immunohistochemical staining in 37 CSG, 88 CAG, 77 IM, 51 DYS, 165 GC and 8 normal tissue samples. Quantitative real-time PCR (qRT-PCR) and western blotting were used to detect the level of MZF1 in gastric cell lines, 15 normal tissues and 34 GC samples, as well as 2 groups of paired primary GC and adjacent normal samples. Results: Reduced MZF1 expression was detected in most GC cells and tissues. Among the gastric tissues consisting of various stages of lesions (normal, CSG, CAG, IM, DYS and GC), MZF1 protein expression was downregulated in precancerous lesions and GC. The data from clinical analyses showed that decreased MZF1 expression was correlated with tumour invasion (p = 0.044), lymph node metastasis (p = 0.048) and poor prognosis of GC patients (p = 0.003). Moreover, MZF1 was identified as an independent prognostic biomarker for GC patients in multivariate Cox regression analysis (p = 0.009). Conclusion: Downregulation of MZF1 was associated with gastric tumourigenesis, which may be a novel early predictive and prognostic biomarker in GC patients.

Decreased long noncoding RNA MIR31HG is correlated with poor prognosis and contributes to cell proliferation in gastric cancer.

Long noncoding RNAs (lncRNAs) are emerging as key regulators governing fundamental biological processes, and their disorder expression involves in the development of several human cancers. MIR31HG, an lncRNA located in 9p21.3 and 2166bp in length, has been found to be upregulated in breast cancer and contributes to cell proliferation and invasion. However, the expression pattern and biological function of MIR31HG in gastric cancer are still not well documented. In this study, we found that MIR31HG expression is decreased in gastric cancer tissues and associated with larger tumor size and advanced pathological stage. Patients with lower MIR31HG expression had a relatively poor prognosis. Furthermore, ectopic over-expression of MIR31HG could inhibit gastric cancer (GC) cell proliferation both in vitro and in vivo, while knockdown of MIR31HG by small interfering RNA (siRNA) promoted cell proliferation in GC cells partly via regulating E2F1 and p21 expression. Our findings present that decreased MIR31HG is involved in GC development and could be identified as a poor prognostic biomarker in GC patients.

Correlation of serum levels of endostatin with tumor stage in gastric cancer: a systematic review and meta-analysis.

Background. We performed a systematic review and meta-analysis to study the association between serum endostatin levels and gastric cancer (GC) progression. Method. We searched the MEDLINE, Science Citation Index, Cochrane Library, PubMed, Embase, Current Contents Index, and several Chinese databases for published studies relevant to our study topic. Carefully selected studies were pooled and SMD and its corresponding 95% CI were calculated. Version 12.0 STATA software was used for statistical analysis. Results. Serum endostatin levels were analyzed in 12 case-control studies (736 GC patients and 350 controls). Significant differences in serum endostatin levels were observed between GC patients and the healthy controls (SMD = 1.418, 95% CI = 1.079~1.757, P < 0.001). Importantly, significantly lower levels of serum endostatin were found in I-II grade patients compared to those with III-IV grade tumors (P < 0.001). Further, higher serum endostatin levels were observed in the LN invasion-positive GC subjects in comparison with LN invasion-negative subjects (P < 0.001). Conclusion. Patients with GC exhibited elevated levels of serum endostatin than controls and its level showed a statistical correlation with the more aggressive type of GC, exhibiting invasion and LN metastasis. Thus, serum levels of endostatin being a useful prognostic biomarker for GC patients warrants further investigation.