• HECT E3 ubiquitin ligases
• gastric cancer
• oncoprotein
• tumor suppressor
• ubiquitination

We aimed to investigate the serum concentration of dihydropyrimidinase-like 3 (DPYSL3) in patients with gastric cancer and its clinical significance.

Seventy four patients with gastric cancer from Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, China from October 2018 to April 2019 were selected as the case group. Sixty patients with normal gastric mucosa or mild non-atrophic gastritis were selected as the control group. Serum DPYSL3, CA72-4 and CEA concentrations were measured in both groups.

The serum DPYSL3 concentration in the case group was significantly higher than that in the healthy control group (22.04±9.22 vs. 8.36±4.19 μg/L, P<0.001). The serum DPYSL3 concentration in patients with advanced gastric cancer was significantly higher than that in early gastric cancer (27.09±9.12 vs. 13.04±8.22 μg/L, P<0.01); serum DPYSL3 concentration was significantly correlated with tumor size, TNM stage and differentiation (P<0.05). When the cutoff value was 20.98 μg/L, the serum DPYSL3 concentration could differentiate the gastric cancer with ROC^AUC 0.882 (95% CI: 0.828–0.937) with sensitivity and specificity of 75% and 94%, respectively. Serum CA72-4 concentration could differentiate the gastric cancer from health controls with ROC^AUC 0.812 (95% CI: 0.734–0.834), serum CEA concentration could differentiate gastric cancer with ROC^AUC 0.612 (95% CI: 0.534 ∼ 0.634). The serum concentrations of DPYSL3, CA72-4 and CEA in gastric cancer patients were increased compared to health controls.

Three serological markers have complementary diagnostic value for gastric cancer. Serum DPYSL3 is a new potential molecular marker for gastric cancer.

• Carcinoembryonic antigen
• Diagnosis
• Dihydropyrimidinase-like 3 protein
• Gastric cancer
• Serum

• Akt/mTOR
• ERK
• High mobility group box 1 (HMGB1)
• RAGE
• gastric cancer
• migration
• proliferation

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are dysregulated in diverse tumors and take a pivotal role in modulating biological processes. In our study, a decreased expression level of LINC00675 in gastric cancer (GC) was first determined by data from The Cancer Genome Atlas (TCGA) and was identified using specimens from GC patients. Then, in vitro and in vivo functional experiments elaborated that LINC00675 could suppress cell proliferation and migration in GC. Multiple differentially expressed genes (DEGs) in LINC00675-overexpressing cells were identified through RNA sequencing analysis. An RNA-binding protein immunoprecipitation (RIP) assay was conducted to reveal that LINC00675 competitively bound with lysine-specific demethylase 1 (LSD1). A coimmunoprecipitation (coIP) assay indicated that LINC00675 overexpression may strengthen the binding of LSD1 and H3K4me2, whereas the chromatin immunoprecipitation (ChIP) assay results verified lower expression of H3K4me2 at the sprouty homolog 4 (SPRY4) promoter region. Together, our research identified that LINC00675 was remarkably downregulated in GC tissues and cells relative to nontumor tissues and cells. LINC00675 could repress GC tumorigenesis and metastasis via competitively binding with LSD1 and intensifying the binding of LSD1 and its target H3K4me2. Importantly, this contributed to attenuated binding of H3K4me2 at the promoter region of oncogene SPRY4 and suppressed SPRY4 transcription, thus suppressing GC cell proliferation and migration.

• H3K4me2
• LINC00675
• LSD1
• SPRY4
• gastric cancer

The aberrant expression of long non-coding RNAs (lncRNAs) plays a pivotal role in the development and progression of multiple cancers, including gastric cancer (GC). However, the underlying molecular mechanisms of lncRNA HCG18 in GC remain unknown.

The expression levels of HCG18, HNF1A, microRNA-152-3p (miR-152-3p), and DNAJB12 were determined by RT-qPCR. Cell viability, migration, and invasion were assessed by CCK-8, wound healing, and transwell assays, respectively. The interaction between miR-152-3p and HCG18 or DNAJB12 was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay. The correlation between the gene expression levels was analyzed using Pearson’s correlation coefficient. Western blot was used to measure the levels of HNF1A, DNAJB12, epithelial-mesenchymal transition (EMT) proteins (E-cadherin and Vimentin), and proliferation-related protein (PCNA).

It was found that HCG18 was upregulated in GC tissues and cell lines, and knockdown of HCG18 inhibited the proliferation, migration, and invasion of GC cells. Patients with high HCG18 expression had a shorter overall survival time compared with those with low HCG18 expression. In addition, transcription factor HNF1A could bind to the HCG18 promoter to facilitate its transcription. The upregulation of HCG18 could abolish the inhibitory effect of miR-152-3p overexpression on GC cell progression. Furthermore, DNAJB12 was demonstrated to be a target gene of miR-152-3p in GC cells, and HCG18 enhanced DNAJB12 expression by competitively binding with miR-152-3p. Finally, rescue assays proved that overexpression of DNAJB12 partially restored HCG18 knockdown-attenuated progression of GC cells.

Our results demonstrated that HNF1A-induced HCG18 overexpression promoted GC progression by competitively binding with miR-152-3p and upregulating DNAJB12 expression. These findings might provide potential treatment strategies for patients with GC.

• DNAJB12
• HCG18
• HNF1A
• gastric cancer
• miR-152-3p

The three dominant recurrence patterns of gastric cancer are peritoneal, hematogenous, and nodal recurrence. Correlation between initial recurrence site and prognosis is poorly understood, particularly after standardization of postoperative S‐1 adjuvant chemotherapy.

We analyzed a multi‐institutional database of 3484 patients who underwent gastrectomy for gastric cancer between 2010 and 2014. Patients who experienced recurrences after curative gastrectomy classified into peritoneal, hematogenous, or nodal recurrence groups, according to their initial recurrence sites, and their prognoses were compared.

We included 313 patients in the analysis, of whom 190 patients (63%) were treated with postoperative adjuvant chemotherapy. Pathological disease states were stage I: n = 20 (6%), stage II: n = 62 (20%), and stage III: n = 231 (74%). Patients were categorized into groups by peritoneal (n = 127), hematogenous (n = 123), and nodal (n = 63) recurrence. The peritoneal recurrence group tended to have longer recurrence‐free survival, but shorter post‐recurrence survival, than the other two groups. Median disease‐specific survival after curative resection by group were peritoneal: 25.8 months, hematogenous: 29.0 months, and nodal: 27.8 months (peritoneal vs hematogenous, P = .152; hematogenous vs nodal, P = .955; peritoneal vs nodal, P = .213).

Prognoses after curative resection for gastric cancer were similar among patients with peritoneal, hematogenous, or nodal recurrences.

• gastric cancer
• prognosis
• recurrence

• Gastric cancer
• hepatic metastasis
• peritoneal metastasis
• xenograft

• EZH2
• LINC00460
• LSD1
• gastric cancer
• proliferation

To explore the regulatory effects of circZNF609 on proliferative and migratory capacities of gastric cancer (GC) and its underlying mechanism.

Expression level of circZNF609, CDK6 and miR-483-3p in GC tissues and cells were detected qRT-PCR verification. CCK-8 and transwell assay were conducted the cell viability and migratory capacities of GC cells. Dual luciferase assay was enrolled to confirm the interaction among circZNF609, CDK6 and miR-483-3p. Western blot was used to detect the protein level of CDK6.

Expression levels of circZNF609 were higher in GC patients by qRT-PCR.GC patients with higher expression of circZNF609 were expected to have a higher TNM stage and lower 5-year survival than those with lower expression. ROC curves showed a well diagnostic value of circZNF609 in GC. Treatment of RNase R in GC cells downregulated the expression of ZNF609, whereas circZNF609 expression did not change. Furthermore, cytoplasmic expression of circZNF609 was higher than those of nuclear expression. Besides, biological experiments indicated that overexpression of circZNF609 promoted the proliferative and migratory capacities of GC cells. To demonstrate the underlying mechanism of circZNF609, we found that circZNF609 bound to miR-483-3p, which presented a lower expression in GC tissues than that of paracancerous tissues. Both circZNF609 and miR-483-3p could bind to Ago2, suggesting that circZNF609 may act as a sponge of miR-483-3p. In addition, the effect of overexpressed circZNF609 on cellular behaviors of GC cells were partly reversed by overexpression of miR-483-3p. Bioinformatics suggested that CDK6 has a potential binding site with miR-483-3p. The expression of CDK6 markedly increased in GC tissues and cells, which was negatively correlated with miR-483-3p expression. Dual-luciferase reporter gene results indicated that miR-483-3p could bind to the 3’-UTR of CDK6. Moreover, miR-483-3p downregulated CDK6 at both mRNA and protein levels. Overexpression of miR-483-3p inhibited proliferative and migratory capacities of GC cells, which were reversed by CDK6 overexpression.

In summary, the expression of circZNF609 is upregulated in GC. CircZNF609 can be used as the sponge of miR-483-3p to regulate the expression level of CDK6, thus participating in the progression of GC by regulating the proliferative and migratory capacities of GC cells.

• CDK6
• MiR-483-3p
• circZNF609
• gastric cancer
• migration
• proliferation

• gastric cancer
• matrix metalloproteinase 14
• prognosis
• prospero homeobox protein 1
• survival

Gastric cancer (GC) is the fourth most common tumor and the second most common cause of cancer-associated mortality worldwide. Current tumor biomarkers for GC, such as serum carcinoembryonic antigen and carbohydrate antigen 19-9, are not ideal due to their limited role as prognostic indicators for GC. Proteasome subunit α7 (PSMA7) is a multifunctional protein, which has been revealed to be involved in the development and progression of various types of malignancy. However, little is known about the role of PSMA7 in GC. In the present study, PSMA7 was identified to be overexpressed at the mRNA and protein levels in GC tissues, compared with in non-tumor tissues, using reverse transcription-quantitative PCR and immunohistochemistry. Furthermore, PSMA7 expression is associated with tumor invasion, lymph node metastasis, distant metastasis, and Tumor-Node-Metastasis stage. Univariate and multivariate Cox regression analysis identified that PSMA7 expression is an independent prognostic factor for poor survival. Kaplan-Meier survival curves revealed that high PSMA7 expression is associated with a poor prognosis in patients with GC. Overall, the results of the present study suggested that PSMA7 may be a promising biomarker for the prognosis of GC, and may represent a new diagnostic marker and molecular therapeutic target for GC.

• gastric cancer
• prognosis
• proteasome subunit α7

• ELF3
• IRF6
• ZEB1
• gastric cancer
• transcriptional regulation

• Chromosomal instability
• Gastric cancer
• Glycerophospholipids
• Lipidomics profile
• Metabolomics

Podocalyxin‐like protein (PODXL), a transmembrane glycoprotein with anti‐adhesive properties, is associated with an aggressive tumor phenotype and poor prognosis of several cancers. To elucidate the biological significance of PODXL and its molecular mechanism in gastric cancer (GC), we investigated the expression of PODXL in GC samples and assessed its effects on biological behaviors and the related signaling pathways in vitro and in vivo. Moreover, the possible and closely interacted partners of PODXL were identified. Our data showed that the protein or mRNA level of PODXL was significantly upregulated in tissues or serum of GC patients compared with normal‐appearing tissues (NAT) or those of healthy volunteers. Overall survival (OS) curves showed that patients with high PODXL levels in tissues or serum had a worse 5‐year OS. In vitro, restoring PODXL expression promoted tumor progression by increasing cell proliferation, colony formation, wound healing, migration and invasion, as well as suppressing the apoptosis. Furthermore, the PI3K/AKT, NF‐κB and MAPK/ERK signaling pathways were activated. There was a significant positive correlation between PODXL and RUN and FYVE domain containing 1 (RUFY1) expression in tissues or serum. Subsequent mass spectrometry analysis, co‐immunoprecipitation assays and western blot analysis identified PODXL/RUFY1 complexes in GC cells, and silencing RUFY1 expression in GC cells significantly attenuated PODXL‐induced phenotypes and their underlying signaling pathways. Our results suggested that PODXL promoted GC progression via a RUFY1‐dependent signaling mechanism. New GC therapeutic opportunities through PODXL and targeting the PODXL/RUFY1 complex might improve cancer therapy.

• Mechanism
• Podocalyxin-like
• RUN and FYVE domain containing 1
• gastric cancer
• progression

Matrix metalloproteinases (MMPs), endopeptidases with diverse biochemical functions, can promote cancer cell invasion and metastasis by degrading the extracellular matrix. A high matrix metalloproteinase-14 (MMP-14) expression in gastric cancer tissue has been associated with metastasis and poor prognosis. To further understand this association, we investigated serum MMP-14 as a biomarker in gastric cancer patients. The patient cohort consisted of 240 gastric adenocarcinoma patients who underwent surgery at Helsinki University Hospital, Finland, between 2000 and 2009. We determined the soluble MMP-14 serum levels using an enzyme-linked immunosorbent assay. We then calculated the associations between serum levels and clinicopathologic variables using the Mann-Whitney U-test or the Kruskal-Wallis test. We constructed survival curves using the Kaplan-Meier method and calculating the hazard ratios using the Cox proportional hazard model. We revealed a positive association between a high serum MMP-14 level and stages III–IV (p = 0.029), and between a high serum MMP-14 and distant metastasis (p = 0.022). Patients with a low serum MMP-14 had a 5-year disease-specific survival of 49.2% (95% confidence interval [CI] 45.5–52.9), whereas patients with a high serum MMP-14 had a 5-year survival of 22.1% (95% CI 15.2–29.0; p = 0.001). High serum MMP-14 was a statistically significant prognostic factor among patients with an intestinal type of cancer (hazard ratio [HR] 3.54; 95% CI 1.51–8.33; p = 0.004), but not among patients with a diffuse type. The serum MMP-14 level remained an independent prognostic factor in our multivariate survival analysis (HR 1.55; 95% CI 1.02–2.35; p = 0.040). This study indicates for the first time that high serum soluble MMP-14 levels in gastric cancer serves as a marker for a poor prognosis, possibly indicating the presence of distant metastases.

• Adenocarcinoma/blood
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Aged
• Biomarkers, Tumor/blood
• Disease-Free Survival
• Female
• Finland/epidemiology
• Follow-Up Studies
• Humans
• Male
• Matrix Metalloproteinase 14/blood
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Proteins/blood
• Retrospective Studies
• Stomach Neoplasms/blood
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Survival Rate

• FGFR1
• Gastric cancer
• epithelial to mesenchymal transition
• peritoneal dissemination

Cervical cancer is the fourth most prevalent malignancy in females worldwide. Early diagnosis is key to improving survival rates. Molecular biomarkers are an important method for diagnosing a number of types of cancer, including cervical cancer. The present study utilized public data from three mRNA microarray datasets and one microRNA dataset to analyze the key genes involved in cervical cancer. The mRNA and microRNA expression profile datasets (GSE9750, GSE46857, GSE67522 and GSE30656) were downloaded from the Gene Expression Omnibus database (GEO). Differentially expressed genes (DEGs) and microRNAs (DEMs) were screened using the online tool GEO2R. By using the DEGs consistent across the three mRNA datasets, a functional and pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed and module analysis performed using the Search Tool for the Retrieval of Interacting Genes. Validated target genes of the DEMs were identified using the miRecords website. Using the identified target genes of the DEMs, a survival analysis was performed using the OncoLnc online tool. A total of 73 DEGs and 19 DEMs were screened from the microarray expression profile datasets. ‘Integrin-mediated’, ‘proteolysis’ and ‘phosphoinositide 3 kinase-protein kinase 3’ signaling pathways were the most enriched in the DEGs. Three of the DEGs, including Ras homolog family member B (RhoB), stathmin 1 (STMN1) and cyclin D1 (CCNB1) were validated DEM target genes. The OncoLnc survival analysis identified that RhoB was associated with a significantly longer overall survival, whereas STMN1 was associated with a significantly reduced overall survival time in patients with cervical cancer. Finally, data from The Cancer Genome Atlas revealed an association between the mRNA expression levels of RhoB and STMN1, and the overall survival time for patients with cervical cancer. In conclusion, RhoB and STMN1 were identified as key genes that may provide potential targets for cervical cancer diagnosis and treatment.

• biomarker
• cervical cancer
• microarray
• survival analysis

Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally cause cancer-related death. Metastasis establishment is affected by various conditions, such as tumor location, hemodynamics and organotropism. While digestive cancers may share a primary site, certain cases develop hematogenous metastasis with the absence of peritoneal metastasis, and vice versa. Numerous studies have revealed the clinicopathological risk factors for hematogenous metastasis from GC, such as vascular invasion, advanced age, differentiation, Borrmann type 1 or 2 and expansive growth. Recently, molecular mechanisms that contribute to metastatic site determination have been elucidated by advanced molecular biological techniques. Investigating the molecules that specifically participate in metastasis establishment in distinct secondary organs will lead to the development of novel biomarkers for patient stratification according to their metastatic risk and strategies for preventing and treating distinct metastases. We reviewed articles related to the molecular landscape of hematogenous metastasis from GC.

• Gastric cancer
• Hematogenous metastasis
• Hepatic metastasis
• Molecular mechanism
• Biomarker
• Premetastatic niche

• ERK
• Gastric cancer
• Gastrin
• P65
• miR23a/27a/24 cluster

• BCL6
• Cell cycle
• Gastric cancer
• miR-519d-3p
• miRNA

Here, we employed a bioinformatics approach to identify novel molecular determinants to predict tumor progression and overall survival in gastric cancer patients. In particular, we directly assessed whether nuclear-derived mRNA species encoding proteins involved in mitochondrial protein translation and OXPHOS are able to successfully predict clinical outcome in gastric cancer. As such, using in silico validation, we have now established the prognostic value of these mitochondrial biomarkers, in a defined population of gastric cancer patients. In this context, we interrogated 5 year follow-up data collected from a group of N = 359 gastric cancer patients. Importantly, in this group of cancer patients, Ki67 and PCNA (conventional markers of cell proliferation) were associated with tumor progression, as might be expected. Using this simplified informatics approach, we identified ∼75 new individual mitochondrial gene probes that effectively predicted tumor progression, with hazard-ratios (HR) of up to 2.22 (p < 2.1e-10). These mitochondrial mRNA transcripts included heat shock proteins/chaperones, membrane proteins, anti-oxidants, enzymes involved in genome maintenance, as well as mitochondrial ribosomal proteins (MRPs) and numerous members of the OXPHOS complexes. In addition, we combined 8 mitochondrial protein transcripts (NDUFS5, VDAC3, ATP5O, IMMT, MRPL28, COX5B, MRPL52, PRKDC), to generate a compact gastric mitochondrial gene signature, associated with a HR of 2.77 (p = 1.4e-14). As a result of this analysis and validation, we strongly suggest that proteins involved in mitochondrial protein translation and OXPHOS should be considered as targets for new drug discovery, for the treatment of gastric cancers. The mitochondrial markers we identified here could also be used as companion diagnostics, to predict clinical outcomes, as well as the patient response to therapy. This should allow a more successful and personalized approach to gastric cancer diagnosis and therapy.

• gastric cancer
• mitochondrial biomarkers
• overall survival
• tumor progression