• Gastric cancer
• Mechanisms
• Melatonin
• Targeted therapy

• Humans
• Melatonin/therapeutic use
• Melatonin/pharmacology
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/pathology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/genetics
• Animals
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• MicroRNAs/metabolism
• MicroRNAs/genetics
• Cell Proliferation/drug effects
• Apoptosis/drug effects

• Cancer
• Pan-cancer analysis
• Phosphorylation
• Prognosis
• eEF2K

• Humans
• Elongation Factor 2 Kinase/metabolism
• Elongation Factor 2 Kinase/genetics
• Prognosis
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/mortality
• Neoplasms/pathology
• Phosphorylation
• Gene Expression Regulation, Neoplastic

• B1617 Introduced Talents and Doctoral start-up funding from Tianjin Medical University Cancer Institute and Hospital
• Z-A20230026 2023 Self-funded research project of Health Commission of Autonomous Region
• YXCXJH2024003 Foundation of Graduate Innovation of the Affiliated Hospital of Youjiang Medical University for Nationality
• BS20224120 Foundation of Baise city Scientific Research & Technology Development Plan
• BS20193220 Foundation of Baise city Scientific Research & Technology Development Plan
• Guiweikejiaofa [2020]-15 Foundation for Medical High-level Academic Leaders
• 2020-3-2 Foundation for Bose Talent Highland
• 2024 Foundation for Building Projects of Guangxi Bagui Scholars
• [2022]-NO.21 Key Laboratory of Molecular Pathology (Hepatobiliary Diseases) of Guangxi and the Key La-boratory of Tumor Molecular Pathology of Guangxi Colleges & Universities
• 2019AC20043 Natural Science Foundation of Guangxi Zhuang Autonomous Region
• R20196304 Research Foundation of the Affiliated Hospital of Youjiang Medical University for Nationality
• JGY2020165 Foundation of Guangxi Graduate Education Innovation Plan

• array-based analysis
• gastric cancer
• gastric intramucosal neoplasia
• genome-wide study
• messenger RNA
• somatic copy number alteration

• Humans
• DNA Copy Number Variations/genetics
• Genome-Wide Association Study
• Mutation
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Chromosomal Instability

• colorectal cancer
• family history
• gastric adenoma
• gastric cancer

• Humans
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/genetics
• Risk
• Stomach Neoplasms/etiology
• Stomach Neoplasms/genetics
• Adenoma/etiology
• Adenoma/genetics
• Risk Factors

• 2020R1A2C1010786 Ministry of Science and ICT, South Korea
• 2020R1A5A2019210 Ministry of Science and ICT, South Korea

• colonoscopy
• colorectal neoplasms
• cancer screening
• gastric neoplasms

• Adenoma/diagnosis
• Aged
• Case-Control Studies
• Cecum
• Colonoscopy/adverse effects
• Colorectal Neoplasms/diagnosis
• Humans
• Prospective Studies
• Risk Factors
• Stomach Neoplasms/diagnosis

The survival outcomes of younger patients with gastric cancer (GC) have remained controversial. This study explores the clinicopathological characteristics, survival outcomes, and genetic alterations of younger and older patients with GC.

Patients with GC were identified from the China National Cancer Center Gastric Cancer Database (NCCGCDB) during 1998–2018. Survival analysis was conducted using Kaplan–Meier estimates and Cox proportional hazards models. Sequencing datasets were enrolled from The Cancer Genome Atlas (TCGA) and Memorial Sloan–Kettering Cancer Center (MSKCC) databases.

A total of 1146 younger (<40 years of age) and 16,988 older (≥40 years of age) cases were included in the study. Younger patients had more poorly differentiated lesions than older patients (53.7% vs. 33.8%, respectively; p < 0.0001), and were more often pTNM stage IV (19.5% vs. 11.8%, respectively; p < 0.001). The 5‐year overall survival (OS) of patients from the NCCGCDB increased from 1998 to 2018. Younger patients with pTNM stage III had a lower survival rate than older patients (p = 0.014), while no differences by age were observed at other stages. The mutation frequency of the LRP1B, GNAS, APC, and KMT2D genes was higher for older than younger patients (p < 0.05 for all genes). While not significantly different, younger patients from the TCGA and MSKCC databases were more likely to have CDH1, RHOA, and CTNNB1 gene mutations.

A stable proportion and improved survival of younger patients were reported using NCCGCDB data. Younger patients with pTNM stage III had lower rates of survival than older patients. Distinct molecular characteristics were identified in younger GC patients which may partly explain the histopathology and prognosis specific to this subpopulation.

The amyloid conformation is considered a fundamental state of proteins and the propensity to populate it a generic property of polypeptides. Multiple proteome-wide analyses addressed the presence of amyloidogenic regions in proteins, nurturing our understanding of their nature and biological implications. However, these analyses focused on highly aggregation-prone and hydrophobic stretches that are only marginally found in intrinsically disordered regions (IDRs). Here, we explore the prevalence of cryptic amyloidogenic regions (CARs) of polar nature in IDRs. CARs are widespread in IDRs and associated with IDPs function, with particular involvement in protein–protein interactions, but their presence is also connected to a risk of malfunction. By exploring this function/malfunction dichotomy, we speculate that ancestral CARs might have evolved into functional interacting regions playing a significant role in protein evolution at the origins of life.

• APR, Aggregation-prone region
• Aggregation
• Amyloid
• CARs, Cryptic amyloidogenic regions
• CD, Circular dichroism
• CR, Congo red
• Evolution
• FTIR, Fourier transform infrared
• IDPs, Intrinsically disordered proteins
• IDRs, Intrinsically disordered regions
• Intrinsically disordered proteins
• PBS, Phosphate buffer saline
• PPI, Protein-protein interactions
• Protein disorder
• Protein–protein interactions
• Rb, Retinoblastoma associated proteins
• RbC, Core region of Rb
• TEM, Transmission electron microscopy
• Th-T, Thioflavin-T

• Mutation
• TP53
• gastric cancer
• meta-analysis
• metastasis

The Wnt signaling pathway plays important roles in embryonic development, homeostatic processes, cell differentiation, cell polarity, cell proliferation, and cell migration via the β-catenin binding of Wnt target genes. Dysregulation of Wnt signaling is associated with various diseases such as cancer, aging, Alzheimer’s disease, metabolic disease, and pigmentation disorders. Numerous studies entailing the Wnt signaling pathway have been conducted for various cancers. Diverse signaling factors mediate the up- or down-regulation of Wnt signaling through post-translational modifications (PTMs), and aberrant regulation is associated with several different malignancies in humans. Of the numerous PTMs involved, most Wnt signaling factors are regulated by ubiquitination and deubiquitination. Ubiquitination by E3 ligase attaches ubiquitins to target proteins and usually induces proteasomal degradation of Wnt signaling factors such as β-catenin, Axin, GSK3, and Dvl. Conversely, deubiquitination induced by the deubiquitinating enzymes (DUBs) detaches the ubiquitins and modulates the stability of signaling factors. In this review, we discuss the effects of ubiquitination and deubiquitination on the Wnt signaling pathway, and the inhibitors of DUBs that can be applied for cancer therapeutic strategies.

• Wnt signaling
• cancer
• deubiquitinating enzymes
• inhibitor
• small molecules
• ubiquitination

Prognostication of patients with colorectal cancer (CRC) currently relies on tumor-node-metastasis (TNM) staging but clinical outcomes of patients of the same histoclinical stage are heterogeneous. It is therefore imperative to devise novel molecular tests to stratify CRC patients. Our previous work demonstrated that eukaryotic elongation factor-2 kinase (EEF2K) is a tumor suppressor in CRC. Herein, we investigated EEF2K expression in CRC and determined its relationship with clinicopathological parameters.

Quantitative RT-PCR and Westerns blots were used to examine EEF2K expression in primary tumor and the adjacent non-tumor tissues of CRC patients (n = 20). Kaplan-Meier curves and Cox regression analysis were used to assess the association between clinical outcomes of CRC patients and EEF2K protein expression determined by immunohistochemistry on tissue microarray (n = 151).

EEF2K was significantly downregulated at both mRNA and protein levels in tumors of CRC patients. Univariate Cox regression analysis revealed that CRC patients with high tumor grade, advanced TNM staging and low EEF2K expression were associated with worse overall survival. Multivariate analysis further demonstrated that low EEF2K expression was an independent factor for predicting poorer overall survival in CRC patients (p = 0.014; Hazard ratio = 2.951; 95% confidence interval: 1.240–7.024). The 5-year survival rate was 82.8% in the EEF2K-high-expression group versus 63.9% in the EEF2K-low-expression group (p = 0.0118). The association of overall survival with EEF2K expression in CRC patients was verified in The Cancer Genome Atlas (TCGA) cohort.

EEF2K is downregulated in CRC and its expression can be employed as a prognostic marker for CRC patients independent of TNM staging.

The online version of this article (10.1186/s12885-019-5873-0) contains supplementary material, which is available to authorized users.

• Biomarker
• Colon cancer
• EEF2K
• Survival
• TNM staging

• Diffuse-type gastric cancer
• Immune checkpoint inhibitor
• Microsatellite unstable
• PD-L1
• PIK3CA
• Patient-derived xenograft
• Primary culture
• Temsirolimus
• mTOR inhibitor

• Animals
• Humans
• Mice
• Microsatellite Instability
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/pathology
• TOR Serine-Threonine Kinases/antagonists & inhibitors

• JP15K06832 Japan Society for the Promotion of Science
• JP25253081 Japan Society for the Promotion of Science
• JP16H06276 Japan Society for the Promotion of Science
• 16K08661 Japan Society for the Promotion of Science
• AA005 Japan Society for the Promotion of Science
• JP17ck0106017 Japan Agency for Medical Research and Development
• 221S0001 Ministry of Education, Culture, Sports, Science and Technology
• KRIBB Research Initiative Program Korea Research Institute of Bioscience and Biotechnology

To study cancer hotspot mutations by next-generation sequencing (NGS) in stool DNA from patients with different gastrointestinal tract (GIT) neoplasms.

Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by using the PSP^® Spin Stool DNA Plus Kit. For each sample, 20 ng of DNA was used to construct sequencing libraries using the Ion AmpliSeq Cancer Hotspot Panel v2 or Ion AmpliSeq Colon and Lung Cancer panel v2. Sequencing was performed on Ion PGM. Torrent Suite Software v.5.2.2 was used for variant calling and data analysis.

NGS was successful in assaying 72 GIT samples and 13 healthy controls, with success rates of the assay being 78% for stomach neoplasia and 87% for colorectal tumors. In stool specimens from patients with gastric neoplasia, five hotspot mutations were found in APC, CDKN2A and EGFR genes, in addition to seven novel mutations. From colorectal patients, 20 mutations were detected in AKT1, APC, ERBB2, FBXW7, KIT, KRAS, NRAS, SMARCB1, SMO, STK11 and TP53. Healthy controls did not exhibit any hotspot mutations, except for two novel ones. APC and TP53 were the most frequently mutated genes in colorectal neoplasms, with five mutations, followed by KRAS with two mutations. APC was the most commonly mutated gene in stools of patients with premalignant/benign GIT lesions.

Our results show that in addition to colorectal neoplasms, mutations can also be assayed from stool specimens of patients with gastric neoplasms.

• Stool DNA
• Next-generation sequencing
• Mutations
• Gastric neoplasia
• Colorectal neoplasia

• Adult
• Aged
• Aged, 80 and over
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• DNA/isolation & purification
• DNA Mutational Analysis/methods
• Early Detection of Cancer/methods
• Feces
• Female
• Finland
• High-Throughput Nucleotide Sequencing/methods
• Humans
• Male
• Middle Aged
• Mutation
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics

• Colorectal neoplasia
• Family history
• Gastric cancer

• Colonoscopy
• Colorectal Neoplasm
• Gastric Neoplasm
• Young

• Adult
• Age Factors
• Aged
• Colonoscopy
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/epidemiology
• Cross-Sectional Studies
• Endoscopy, Digestive System
• Female
• Humans
• Male
• Middle Aged
• Odds Ratio
• Prevalence
• Retrospective Studies
• Risk Factors
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/epidemiology

• Adenomatous polyposis coli (APC)
• Cell cycle
• Gastric adenocarcinomas
• Immunoreactivity
• Mutation

• Adenomatous Polyposis Coli/diagnosis
• Adenomatous Polyposis Coli/genetics
• Adenomatous Polyposis Coli Protein/genetics
• Adolescent
• Adult
• Aged
• Body Mass Index
• Case-Control Studies
• Down-Regulation
• Exons
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Mutation
• Sequence Analysis, DNA
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics
• Young Adult

• Department of Biotechnology , Ministry of Science and Technology

Loss of function of adenomatous polyposis coli (APC) has been reported in cancer. The two promoters of APC, 1A and 1B also have roles in cancer. But, the epigenetic role of APC promoters is not yet clear in gallbladder cancer (GBC) and gallstone diseases (GSD). We undertook this study to determine the epigenetic role of APC in GBC and GSD.

Methylation-specific (MS)-PCR was used to analyze the methylation of APC gene. The expression of APC gene was studied by semi-quantitative PCR, real-time PCR and immunohistochemistry (IHC) in GBC, GSD and adjacent normal tissues.

Of the two promoters, APC 1A promoter was found methylated in 96 per cent GBC (P=0.0155) and 80 per cent GSD (P=0.015). Exon 1 was downregulated in grade II (P=0.002) and grade III (P=0.0001) of GBC, while exon 2 was normally expressed. Scoring analysis of IHC revealed 0 or negativity in 34.48 per cent (P=0.057) and 1+ in 24.14 per cent (P=0.005) GBC cases suggesting loss of APC expression.

The present findings indicate epigenetic silencing of APC in advanced GBC. The methylation pattern, followed by expression analysis of APC may be suggested for diagnostic, prognostic and therapeutic purposes in GBC in future.

The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a useful approach for cancer therapy. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/β-catenin signaling, and which plays an important role in transcriptional regulation by β-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here, we show that elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in AGS and MKN28 cells, but also reduced the migration and invasion ability of these cells. Furthermore, an in vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target.

• CCAR1
• Wnt signaling
• gastric cancer
• metastasis
• β-catenin

• Aged
• Animals
• Apoptosis/genetics
• Apoptosis Regulatory Proteins/genetics
• Apoptosis Regulatory Proteins/metabolism
• Cell Cycle/genetics
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Kaplan-Meier Estimate
• Male
• Mice
• Middle Aged
• Prognosis
• RNA Interference
• RNA, Small Interfering/genetics
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Wnt Signaling Pathway
• beta Catenin/metabolism

Background/Aims. To evaluate the incidence of gastric adenoma and gastric cancer in colorectal cancer patients, as well as the clinicopathological features that affect their incidence. Methods. Among patients who underwent surgery after being diagnosed with colorectal cancer between January 2004 and December 2013 at Chungnam National University Hospital, 142 patients who underwent follow-up upper gastrointestinal endoscopy were assigned to the patient group. The control group included 426 subjects randomly selected. The patient group was subdivided into two: one that developed gastric adenoma or cancer and one that did not. Clinicopathological characteristics were compared between these groups. Results. In total, 35 (24.6%) colorectal cancer patients developed a gastric adenoma or gastric cancer, which was higher than the number in the control group (20 [4.7%] patients; p < 0.001). Age, alcohol history, and differentiation of colorectal cancer were associated with higher risks of gastric adenoma or gastric cancer, with odds ratios of 1.062, 6.506, and 5.901, respectively. Conclusions. In colorectal cancer patients, screening with upper gastrointestinal endoscopy is important, even if no lesions are noted in the upper gastrointestinal tract at colorectal cancer diagnosis. Endoscopic screening is particularly important with increasing age, history of alcohol consumption, and poor cancer differentiation.

Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-Kras^G12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-catenin^S37A and WNT1 stimulated the progression of premalignant pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-β-catenin^S37A or RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P < .05). Ectopic expression of active β-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the β-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/β-catenin signaling pathway in pancreatic cancer cells. Nuclear β-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear β-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P < .01). Knockdown of CYR61 in a β-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/β-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61.

Several novel fusion transcripts were identified by next-generation sequencing in gastric cancer; however, the breakpoint junctions have yet to be characterized. The present study characterized a plethora of APIP-FGFR2 genomic breakpoints in the SNU-16 gastric cancer cell line, which harbored homogeneously staining regions (hsrs) and double minute chromosomes. Oligonucleotide microarrays revealed high-level amplifications at chromosomes 8q24.1 (0.8 Mb region), 10q26 (1.1 Mb) and 11p13 (1.1 Mb). These amplicons contained MYC and PVT1 at chromosome 8q24.1, BRWD2, FGFR2 and ATE1 at chromosome 10q26, and 24 genes, including APIP, CD44, RAG1 and RAG2, at chromosome 11p13. Based on these findings, reverse transcription-polymerase chain reaction (PCR) was performed using various candidate gene primers to detect possible fusion transcripts, and several products using primer sets for the APIP and FGFR2 genes were detected. Eventually, three in-frame and two out-of-frame fusion transcripts were detected. Notably, PCR analysis of the entire genomic DNA detected three distinct genomic junctions. The breakpoints were within intron 5 of APIP, which contained three distinct breakpoints, and introns 5, 7 and 9 of FGFR2. Fluorescence in situ hybridization showed several fusion signals within hsrs using two short probes (~10-kb segments of a bacterial artificial chromosome clone) containing exons 2–5 of APIP or exons 11–13 of FGFR2. Although, for any given fusion, a multiplicity of transcripts is thought to be created by alternative splicing of one rearranged allele, the results of the present study suggested that genomic fusions of APIP and FGFR2 are generated in hsrs with a diversity of breakpoints that are then faithfully transcribed.

• APIP
• FGFR2
• gastric cancer
• genomic amplification
• homogenously staining region

The importance of canonical and non-canonical Wnt signal transduction cascades in embryonic development and tissue homeostasis is well recognized. The aberrant activation of these pathways in the adult leads to abnormal cellular behaviors, and tumor progression is frequently a consequence. Here we discuss recent findings and analogies between Wnt signaling in developmental processes and tumor progression, with a particular focus on cell motility and matrix invasion and highlight the roles of the ARF (ADP-Ribosylation Factor) and Rho-family small GTP-binding proteins. Wnt-regulated signal transduction from cell surface receptors, signaling endosomes and/or extracellular vesicles has the potential to profoundly influence cell movement, matrix degradation and paracrine signaling in both development and disease.

• Wnts
• cancer
• cell invasion
• cell motility
• development
• small GTP-binding proteins

• Colorectal cancer
• Gastric cancer
• Microsatellite instability
• p53

Gastric cancer is one of the most common types of cancer in the world, particularly in underdeveloped countries. The mechanism of gastric cancer is less understood compared with other types of gastrointestinal (GI) cancers. Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor and is a potential tumor suppressor in GI cancers. In this study, we have generated two mouse models, Rosa-Cre;Klf4^fl/fl and Lgr5-Cre;Klf4^fl/fl. KLF4 was deleted by Rosa-Cre in the gastric epithelia cells or by Lgr5-Cre in the antral stem cells in the adult mice. KLF4 deletion resulted in increased proliferating cells and decreased pit mucous cells. Surprisingly, the intestinal goblet cell marker, MUC2, which is not expressed in normal gastric tissues, was strongly induced at the base of the KLF4-deleted antral glands. To understand the clinical relevance of these findings, we analyzed the expression of KLF4 and MUC2 in human gastric cancer. In a subset of human gastric cancer, the expression of KLF4 is negatively associated with MUC2 expression. In conclusion, KLF4 is essential for normal homeostasis of antral stem cells; loss of KLF4 and expression of MUC2 could be important markers for gastric cancer diagnosis.

• cytoreductive surgery
• gastric cancer
• intraperitoneal chemotherapy
• peritoneal carcinomatosis

Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities, including cell proliferation, calcium homeostasis, and cell polarity. The role of Wnt signaling in controlling cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway, which is the best-characterized the multiple Wnt signaling branches. The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway, as many new components of Wnt signaling have been identified and linked to signaling regulation, stem cell functions, and adult tissue homeostasis. Additionally, a substantial body of evidence links Wnt signaling to tumorigenesis of cancer types and implicates it in the development of cancer drug resistance. Thus, a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy. This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease. We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness, tumorigenesis, and cancer drug resistance. Ultimately, we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance.

• Wnt
• cancer
• cancer drug resistance
• cancer stem cells
• canonical Wnt
• cell differentiation
• cell proliferation
• fate determination
• self-renewal
• signal transduction
• stem cells
• tumorigenesis
• β-catenin

• DNA copy number profiling
• Epstein-Barr virus
• Gastric adenocarcinoma
• Gene expression profiling
• Integrative genomics analysis
• Methylation profiling
• Microsatellite instability
• Next-generation sequencing
• Whole-exome sequencing
• Whole-genome sequencing
• miRNA profiling

DIXDC1 (Dishevelled-Axin domain containing 1) is a positive regulator of the Wnt pathway. In the field of cancer research, the role of DIXDC1 is unclear. Our previous in vitro study showed that DIXDC1 enhances β-catenin nuclear accumulation in gastric cancer cell lines. The aim of this study was to detect the expression of DIXDC1 in different histological subtypes of gastric carcinoma and to evaluate the correlation between the expression of DIXDC1 and β-catenin localization and clinicopathological parameters, including patients’ survival.

Immunohistochemical staining was performed to characterize the expression of DIXDC1 and β-catenin in archived materials from 259 cases of gastric carcinoma. The χ2 test and the Fisher’s test were used to analyze correlations between DIXDC1 expression, β-catenin localization, and clinicopathological parameters. Univariate analyses were performed using the Kaplan–Meier method, and the survival difference between groups was assessed by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model.

Positive DIXDC1 staining was detected in tumor cells in 123 of 259 (47.5 %) cases. DIXDC1 expression in gastric carcinoma was significantly correlated with the histological intestinal-type (P < 0.001), the depth of tumor invasion (P < 0.001) and the lymph node metastasis (P = 0.006). In the intestinal-type, DIXDC1 was correlated with the nuclear and cytoplasmic β-catenin expression (P = 0.002). Kaplan–Meier analysis indicated that patients with high DIXDC1 expression had poor disease-specific survival (P < 0.001), especially in the intestinal-type. Moreover, multivariate regression analysis showed that positive expression of DIXDC1 was an independent prognostic predictor of intestinal-type gastric carcinoma.

Our study indicated that DIXDC1 is a significant independent prognostic indicator in intestinal-type gastric carcinoma that plays an important role in carcinogenesis and progression of gastric carcinoma through the Wnt signaling pathway.

• DIXDC1
• Gastric carcinoma
• Immunohistochemistry
• Intestinal-type
• β-catenin

A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor–DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein–protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

• NF-κB
• c-jun/c-fos (AP-1)
• c-myc/max
• polyphenol.
• transcription factor
• β-catenin/Tcf

• Humans
• Plant Extracts/pharmacology
• Polyphenols/pharmacology
• Signal Transduction
• Transcription Factors/metabolism
• Transcriptional Activation/drug effects

• Biomarkers
• Clinical utility
• Epigenetics
• Gastric cancer
• Gene methylation

Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide. Cancer stem cells (CSCs), which were first identified in acute myeloid leukemia and subsequently in a large array of solid tumors, play important roles in cancer initiation, dissemination and recurrence. CSCs are often transformed tissue-specific stem cells or de-differentiated transit amplifying progenitor cells. Several populations of multipotent gastric stem cells (GSCs) that reside in the stomach have been determined to regulate physiological tissue renewal and injury repair. These populations include the Villin+ and Lgr5+ GSCs in the antrum, the Troy+ chief cells in the corpus, and the Sox2+ GSCs that are found in both the antrum and the corpus. The disruption of tumor suppressors in Villin+ or Lgr5+ GSCs leads to GC in mouse models. In addition to residing GSCs, bone marrow-derived cells can initiate GC in a mouse model of chronic Helicobacter infection. Furthermore, expression of the cell surface markers CD133 or CD44 defines gastric CSCs in mouse models and in human primary GC tissues and cell lines. Targeted elimination of CSCs effectively reduces tumor size and grade in mouse models. In summary, the recent identification of normal GSCs and gastric CSCs has greatly improved our understanding of the molecular and cellular etiology of GC and will aid in the development of effective therapies to treat patients.

• Cancer stem cells
• Gastric cancer
• Lgr5
• Villin
• Troy
• Sox2
• CD133
• CD44
• E-cadherin

• Animals
• Antigens, CD
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Cadherins/genetics
• Cadherins/metabolism
• Cell Differentiation
• Cell Proliferation
• Cell Survival
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Epithelial-Mesenchymal Transition
• Helicobacter Infections/complications
• Helicobacter Infections/microbiology
• Helicobacter pylori/pathogenicity
• Humans
• Multipotent Stem Cells/metabolism
• Multipotent Stem Cells/microbiology
• Multipotent Stem Cells/pathology
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/microbiology
• Neoplastic Stem Cells/pathology
• Phenotype
• Risk Factors
• Signal Transduction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy

14-3-3 proteins participate in various cellular processes, including apoptosis, proliferation and malignant transformation. 14-3-3σ, a member of the 14-3-3 protein family, is important in several types of cancer; however, little is known about the clinical significance and biological roles of 14-3-3σ in gastric cancer. The present study analyzed the expression pattern of 14-3-3σ in gastric cancer and investigated its correlation with the prognosis of gastric cancer patients. Furthermore, the association of 14-3-3σ with Ki-67, Bcl-2 and Bax was evaluated. 14-3-3σ was expressed at higher level in gastric cancer tissue compared with healthy gastric tissue, and 14-3-3σ expression was significantly correlated with tumor size and tumor node metastasis stage (P<0.05). To the best of our knowledge, the present study data are the first to suggest that 14-3-3σ expression has been significantly associated with poor prognosis in gastric cancer. Additionally, 14-3-3σ overexpression was positively correlated with Ki-67 and Bcl-2 expression levels. Thus, 14-3-3σ is a potential prognostic marker for gastric cancer patients, and may be involved in regulating the apoptosis and proliferation of gastric cancer cells.

• 14-3-3σ
• apoptosis
• immunohistochemistry
• prognosis
• proliferation

The molecular genetics of gastric carcinoma (GC) dictates their biology and clinical behavior. The two morphologically distinct types of gastric carcinoma by Lauren classification, i.e., intestinal and diffuse cell types, have a significant difference in clinical outcome. These two types of GC have different molecular pathogenetic pathways with unique genetic alterations. In addition to environmental and other etiologies, intestinal type GC is associated with Helicobacter pylori (H. pylori) infection and involves a multistep molecular pathway driving the normal epithelium to intestinal metaplasia, dysplasia, and malignant transformation by chromosomal and/or microsatellite instability (MSI), mutation of tumor suppressor genes, and loss of heterozygosity among others. Diffuse type shows no clear causal relationship with H. pylori infection, but is commonly associated with deficiency of cell-cell adhesion due to mutation of the E-cadherin gene (CDH1), and a manifestation of the hereditary gastric cancer syndrome. Thus, detection of CDH1 mutation or loss of expression of E-cadherin may aid in early diagnosis or screening of diffuse type GC. Detection of certain genetic markers, for example, MSI and matrix metalloproteinases, may provide prognostic information, particularly for intestinal type. The common genetic alterations may offer therapeutic targets for treatment of GC. Polymorphisms in Thymidylate synthase to metabolize 5-fluorouracil, glutathione S-transferase for degradation of Cisplatin, and amplification/overexpression of human epidermal growth factor receptor 2 targeted by monoclonal antibody Trastuzumab, are a few examples. P13K/Akt/mTOR pathway, c-Met pathways, epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor fibroblast growth factor receptor, and micro RNAs are several potential therapeutic biomarkers for GC under investigation.

• Molecular genetics
• Lauren classification
• Intestinal type gastric cancer
• Diffuse type gastric cancer
• Molecular Biomarker

• APC
• Allelic losses
• Ileal neuroendocrine neoplasms
• Mutation
• Polymorphism

Through silencing tumor suppressor genes, epigenetic changes can activate signaling pathways important to cancer development. In this report, we found an epigenetic contribution to the aberrant activation of wnt signaling in human gastric cancer. CXXC4 (CXXC finger protein 4) was identified as a novel target of EZH2 (enhancer of zeste homolog 2), and EZH2 promotes the activation of wnt singaling by downregulating CXXC4 expression. CXXC4 inhibits the growth of gastric cancer cells both in vitro and in vivo through inactivating wnt signaling. In contrast, depletion of CXXC4 activates wnt signaling and promotes the anchorage-independent growth of nontumor gastric epithelial cells. CXXC4 is downregulated in gastric carcinoma tissues and its downregulation is associated with poor outcome of gastric cancer patients (hazard ratio: 5.053, P<0.05). Through its binding to dishevelled (Dvl), CXXC4 stabilizes the destruction complex of β-catenin to inhibit wnt signaling. Two critical amino acid residues in CXXC4, K161 and T162 were found to be important to its binding to Dvl and the growth inhibitory effect of CXXC4. In summary, EZH2 promotes the activation of wnt signaling in gastric carcinogenesis through the downregulation of CXXC4 expression. CXXC4 is a novel potential tumor suppressor directly regulated by EZH2, and its expression is a significant prognosis factor for patients with early stages of gastric cancer.

• Chemoprevention
• Diet
• Epidemiology
• Epigenetic changes
• Gastric cancer
• Genetic alterations
• Helicobacter pylori
• Risk factors

The Wnt signaling pathway is involved in a wide range of embryonic patterning events and maintenance of homeostasis in adult tissues. The pathological role of the Wnt pathway has emerged from studies showing a high frequency of specific human cancers associated with mutations that constitutively activate the transcriptional response of these pathways. Constitutive activation of the Wnt signaling pathway is a common feature of solid tumors and contributes to tumor development, progression and metastasis in various cancers. In this review, the Wnt pathway will be covered from the perspective of urological cancers with emphasis placed on the recent published literature. Regulation of the Wnt signaling pathway by microRNAs (miRNA), small RNA sequences that modify gene expression profiles will also be discussed. An improved understanding of the basic genetics and biology of Wnt signaling pathway will provide insights into the development of novel chemopreventive and therapeutic strategies for urological cancers.