Antibody-drug conjugates in gastric cancer: from molecular landscape to clinical strategies.

Antibody-drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics.

A Brief Review of Recent Theoretical Advances in Fe-Based Catalysts for CO2 Hydrogenation.

Catalytic hydrogenation presents a promising approach for converting CO2 into valuable chemicals and fuels, crucial for climate change mitigation. Iron-based catalysts have emerged as key contributors, particularly in driving the reverse water-gas shift and Fischer-Tropsch synthesis reactions. Recent research has focused on enhancing the efficiency and selectivity of these catalysts by incorporating alkali metal promoters or transition metal dopants, enabling precise adjustments to their composition and properties. This review synthesizes recent theoretical advancements in CO2 hydrogenation with iron-based catalysts, employing density functional theory and microkinetic modeling. By elucidating the underlying mechanisms involving metallic iron, iron oxides, and iron carbides, we address current challenges and provide insights for future sustainable CO2 hydrogenation developments.

Research Progress of Non-Noble Metal Catalysts for Carbon Dioxide Methanation.

The extensive utilization of fossil fuels has led to a rapid increase in atmospheric CO2 concentration, resulting in various environmental issues. To reduce reliance on fossil fuels and mitigate CO2 emissions, it is important to explore alternative methods of utilizing CO2 and H2 as raw materials to obtain high-value-added chemicals or fuels. One such method is CO2 methanation, which converts CO2 and H2 into methane (CH4), a valuable fuel and raw material for other chemicals. However, CO2 methanation faces challenges in terms of kinetics and thermodynamics. The reaction rate, CO2 conversion, and CH4 yield need to be improved to make the process more efficient. To overcome these challenges, the development of suitable catalysts is essential. Non-noble metal catalysts have gained significant attention due to their high catalytic activity and relatively low cost. In this paper, the thermodynamics and kinetics of the CO2 methanation reaction are discussed. The focus is primarily on reviewing Ni-based, Co-based, and other commonly used catalysts such as Fe-based. The effects of catalyst supports, preparation methods, and promoters on the catalytic performance of the methanation reaction are highlighted. Additionally, the paper summarizes the impact of reaction conditions such as temperature, pressure, space velocity, and H2/CO2 ratio on the catalyst performance. The mechanism of CO2 methanation is also summarized to provide a comprehensive understanding of the process. The objective of this paper is to deepen the understanding of non-noble metal catalysts in CO2 methanation reactions and provide insights for improving catalyst performance. By addressing the limitations of CO2 methanation and exploring the factors influencing catalyst effectiveness, researchers can develop more efficient and cost-effective catalysts for this reaction.

Intratumoral immune heterogeneity of prostate cancer characterized by typing and hub genes.

Discordant abundances of different immune cell subtypes is regarded to be an essential feature of tumour tissue. Direct studies in Prostate cancer (PC) of intratumoral immune heterogeneity characterized by immune cell subtype, are still lacking. Using the single sample gene set enrichment analysis (ssGSEA) algorithm, the abundance of 28 immune cells infiltration (ICI) were determined for PC. A NMF was performed to determine tumour-sample clustering based on the abundance of ICI and PFS information. Hub genes of clusters were identified via weighted gene co-expression network analysis (WGCNA). The multivariate dimensionality reduction analysis of hub genes expression matrix was carried out via principal component analysis (PCA) to obtain immune score (IS). We analysed the correlation between clustering, IS and clinical phenotype. We divided the 495 patients into clusterA (n = 193) and clusterB (n = 302) on the basis of ICI and PFS via NMF. The progression-free survival (PFS) were better for clusterA than for clusterB (p < 0.001). Each immune cell subtypes was more abundant in clusterA than in clusterB (p < 0.001). The expression levels of CTAL-4 and PD-L1 were lower in clusterB than in clusterA (p < 0.001 and p = 0.006). We obtained 103 hub genes via WGCNA. In the training and validation cohorts, the prognosis of high IS group was worse than that of the low IS group (p < 0.05). IS had good predictive effect on 5-year PFS. The expression of immune checkpoint genes was higher in the low IS group than in the high IS group (p < 0.01). Patients with low IS and receiving hormone therapy had better prognosis than other groups. The combination of IS and clinical characteristics including lymph node metastasis and gleason score can better differentiate patient outcomes than using it alone. IS was a practical algorithm to predict the prognosis of patients. Advanced PC patients with low IS may be more sensitive to hormone therapy. CXCL10, CXCL5, MMP1, CXCL12, CXCL11, CXCL2, STAT1, IL-6 and TLR2 were hub genes, which may drive the homing of immune cells in tumours and promote immune cell differentiation.

Burden and Trends of IBD in 5 Asian Countries From 1990 to 2019: A Comparison With the United States and the United Kingdom.

BACKGROUND: IBD is becoming a global health challenge, with substantial variations in incidence and death rates between Eastern and Western countries. OBJECTIVE: This study aimed to investigate the burden and trends of IBD in 5 Asian countries, the United States, and the United Kingdom. DESIGN: This was a cross-sectional study. SETTING: Data were obtained from Global Burden of Disease 2019 Study. PATIENTS: Patients with IBD were included. MAIN OUTCOME MEASURES: Incidence, death, and age-standardized rates of IBD were measured. RESULTS: The age-standardized incidence and rates of death from IBD gradually decreased worldwide from 1990 to 2019. The age-standardized incidence rate in the United States decreased from 1990 to 2000 and then increased gradually from 2000 to 2019; the age-standardized incidence rates in the United Kingdom, Mongolia, and China increased gradually from 1990 to 2019, whereas in the Democratic People's Republic of Korea, it decreased from 1990 to 1995 and increased gradually from 1995 to 2019. The age-standardized death rate in the Republic of Korea exhibited a rising trend until 1995, fell significantly up to 2015, and then stabilized from 2015 to 2019. The age-standardized death rate in the United States showed a rising trend until 2007, and then decreased gradually from 2007 to 2019, whereas the rate in the United Kingdom showed a rising trend until 2010 and decreased from 2010 to 2019. The age-standardized death rates in China, Mongolia, the Democratic People's Republic of Korea, and Japan decreased gradually from 1990 to 2019. The age-standardized incidence and death rates in the United States and United Kingdom in recent decades were higher than those in the 5 Asian countries. The peak age-standardized incidence rates in the 7 countries were among people of 20 to 60 years of age. The age-standardized death rates in all 7 countries exhibited rising trends with increasing age, with older individuals, particularly those aged ≥70 years, accounting for the most deaths. LIMITATIONS: Limitations of this study include data from different countries with different quality and accuracy. CONCLUSIONS: There have been large variations in the burdens and trends of IBD between 5 Asian countries, the United States, and the United Kingdom during the past 3 decades. These findings may help policymakers to make better public decisions and allocate appropriate resources. See Video Abstract at http://links.lww.com/DCR/B996 . CARGA Y TENDENCIAS DE LA ENFERMEDAD INFLAMATORIA INTESTINAL EN CINCO PASES ASITICOS DESDE HASTA UNA COMPARACIN CON LOS ESTADOS UNIDOS Y EL REINO UNIDO: ANTECEDENTES:La enfermedad inflamatoria intestinal se está convirtiendo en un desafío en la salud mundial, con variaciones sustanciales en las tasas de incidencia y mortalidad entre los países orientales y occidentales.OBJETIVO:Investigar la carga y las tendencias de la enfermedad inflamatoria intestinal en cinco países asiáticos, EE. UU. y el Reino Unido.DISEÑO:Estudio transversal.ESCENARIO:Estudio de carga global de morbilidad 2019.PACIENTES:Enfermedad inflamatoria intestinal.PRINCIPALES MEDIDAS DE RESULTADO:Incidencia, muerte y tasas estandarizadas por edad de enfermedad inflamatoria intestinal.RESULTADOS:Las tasas de incidencia y muerte estandarizadas por edad de la enfermedad inflamatoria intestinal disminuyeron gradualmente en todo el mundo desde 1990 hasta 2019. La tasa de incidencia estandarizada por edad en los EE. UU. disminuyó de 1990 a 2000 y luego aumentó gradualmente de 2000 a 2019, las tasas en el Reino Unido, Mongolia y China aumentaron gradualmente de 1990 a 2019, mientras que la tasa en la República Popular Democrática de Corea disminuyó de 1990 a 1995 y aumentó gradualmente de 1990 a 2019. La tasa de mortalidad estandarizada por edad en la República de Corea exhibió un tendencia ascendente hasta 1995, cayó significativamente hasta 2015 y luego se estabilizó de 2015 a 2019. La tasa de mortalidad estandarizada por edad en los EE. UU. mostró una tendencia ascendente hasta 2007 y luego disminuyó gradualmente de 2007 a 2019, mientras que la tasa en el Reino Unido mostró una tendencia ascendente hasta 2010 y disminuyó de 2010 a 2019. Las tasas de mortalidad estandarizadas por edad en China, Mongolia, la República Popular Democrática de Corea y Japón disminuyeron gradualmente de 1990 a 2019. La tasa de incidencia estandarizada por edad y mortalidad en los EE. UU. y el Reino Unido en la última década fueron más altas que las de los cinco países asiáticos. Las tasas máximas de incidencia estandarizadas por edad en los siete países se dieron entre personas de 20 a 60 años. Las tasas de mortalidad estandarizadas por edad en los siete países exhibieron tendencias crecientes con el aumento de la edad, y las personas mayores, en particular las de ≥70 años, representaron la mayoría de las muertes.LIMITACIONES:Datos de diferentes países con diferente calidad y precisión.CONCLUSIONES:Ha habido grandes variaciones en las cargas y tendencias de la enfermedad inflamatoria intestinal entre cinco países asiáticos, EE. UU. y el Reino Unido durante las últimas tres décadas. Estos hallazgos pueden ayudar a los formuladores de políticas a tomar mejores decisiones públicas y asignar los recursos apropiados. Consulte Video Resumen en http://links.lww.com/DCR/B996 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Prediction of tissue origin of adenocarcinomas in the esophagogastric junction by DNA methylation.

BACKGROUND: Prediction of tissue origin of esophagogastric junction (EGJ) adenocarcinomas can be important for therapeutic decision, but no molecular marker is available. Here, we aimed to develop such a marker taking advantage of tissue-specific profiles of DNA methylation. METHODS: DNA methylation profiles of gastric adenocarcinomas (GACs) were obtained by an Infinium HumanMethylation450 BeadChip array, and those of esophageal adenocarcinoma (EACs) were obtained from the TCGA database. DNA from formalin-fixed paraffin-embedded (FFPE) samples was analyzed by bisulfite pyrosequencing. RESULTS: In the screening set, 51 of 145,841 CpG sites in CpG islands were methylated at significantly higher levels in 30 GACs compared to those in 30 EACs. Among them, SLC46A3 and cg09177106 were unmethylated in all the 30 EACs. Predictive powers of these two markers were successfully confirmed in an independent validation set (18 GACs and 18 EACs) (SLC46A3, sensitivity = 77.8%, specificity = 100%; cg09177106, sensitivity = 83.3%, specificity = 94.4%), and could be applied to FFPE samples (37 GACs and 18 EACs) (SLC46A3, P = 0.0001; cg09177106, P = 0.0028). On the other hand, EAC-specific markers informative in the FFPE samples could not be isolated. Using these GAC-specific markers, nine of 46 (19.6%) TCGA EGJ adenocarcinomas were predicted to be GACs. CONCLUSIONS: Two GAC-specific markers, SLC46A3 and cg09177106, had a high specificity for identifying the tissue origin of EGJ adenocarcinoma.

The novel role and function of LINC01235 in metastasis of gastric cancer cells by inducing epithelial-mesenchymal transition.

LncRNAs play a vital role in the tumorigenesis of gastric cancer (GC). This study determined that LINC01235 expression has greater fold changes by analyzing TCGA RNA-Seq data. The qRT-PCR assay confirmed that LINC01235 is significantly over-expressed in GC cells and tissues. Additionally, the overall survival analysis showed that patients with a higher LINC01235 expression had a poorer prognosis than those with a lower LINC01235 expression. Univariate Cox regression analysis indicated that high LINC01235 expression is positively correlated with poor prognosis. Moreover, LINC01235 was an independent poor prognostic marker for GC in multivariate Cox analysis. Invitro assays suggested that LINC01235 knockdown suppresses GC cell migration and invasion. GSEA revealed that high LINC01235 expression is strongly enriched in the EMT pathway. Western blotting results revealed that LINC01235 silencing decreases the expression of EMT-induced proteins. In conclusion, LINC01235 can promote GC cell metastasis via EMT and function as a prognostic biomarker.

High flow nasal oxygen versus conventional oxygen therapy in gastrointestinal endoscopy with conscious sedation: Systematic review and meta-analysis with trial sequential analysis.

OBJECTIVES: Although conventional oxygen therapy (COT) is widely used, hypoxemia frequently occurs in gastrointestinal endoscopy with conscious sedation and can lead to life-threatening consequences. High flow nasal oxygen (HFNO) has been applied to improve oxygenation in clinical entities. However, its efficacy to prevent hypoxemia in gastrointestinal endoscopy with conscious sedation has not been evaluated. METHODS: We searched databases to identify randomized controlled trials that compared the efficacy of HFNO with COT in gastrointestinal endoscopy with conscious sedation. The primary outcome was hypoxemia. Meta-analyses with trial sequential analysis were performed using a random-effects model. RESULTS: Eight trials with 3212 patients were included. Compared with COT, HFNO significantly reduced the risk of hypoxemia (eight trials; 3212 patients; risk ratio 0.30; 95% confidence interval [CI] 0.13-0.70). Trial sequential analysis showed that the cumulative Z curve did not cross the monitoring or futility boundaries, nor reach the required information size line, indicating that more trials are needed to reach a definitive conclusion. Subgroup analyses indicated the superiority of HFNO over COT with respect to hypoxemia in patients at low risk and high risk. HFNO further improved the lowest oxygen saturation (four trials; 459 patients; mean difference 2.30, 95% CI 0.84-3.77). CONCLUSIONS: Compared with COT, HFNO can reduce the risk of hypoxemia and improve the lowest oxygen saturation in gastrointestinal endoscopy with conscious sedation. However, the results should be interpreted with caution due to substantial heterogeneity and limited evidence. Further studies are needed to verify the preliminary findings.

[Establishment and Preliminary Analysis of Lung Cancer Cell Line A549 with Stable MAP4 K4 Knockdown].

Objective: To analyze the effect of knocking down MAP4 K4 expression on the proliferation and migration of cancer cells, and to explore its underlining molecular mechanisms. Methods: A stable knockdown MAP4 K4 cell line was constructed and the subcellular localization of the cells was determined with immunofluorescence, cell proliferation assay and cell migration assay. In addition, the effects of down-regulated MAP4 K4 expression were analyzed by examining the difference between the proliferation and migration of cancer cells in the knockdown group and those of the control group. Results: MAP4 K4 was localized in focal adhesion and cell edges in A549 cells. Stable knockdown of MAP4 K4 expression induced cancer cells to grow in clusters and arrested the progression of the cell cycle and cell migration. Further analysis found that knocking down MAP4 K4 expression in A549 cells induced the accumulation of epithelial cell marker E-cadherin, and subsequently, the down-regulation of N-cadherin, a mesenchymal cell marker, thereby disrupting the "cadherin switch" and the epithelial-mesenchymal conversion. Then, the control group and the knockdown group both received the combined treatment of cisplatin at a final concentration of 5 µmol/L and paclitaxel at a final concentration of 20 nmol/L. The stably knocked down MAP4 K4 expressing cells showed significantly enhanced toxicity of chemotherapeutic drugs to cancer cells. Conclusion: The study shows that MAP4 K4 regulates the malignant phenotypes of cancer cells and chemoresistance by regulating "cadherin switch" to promote epithelial-mesenchymal transition in A549 cells.

Proline-rich 11 (PRR11) drives F-actin assembly by recruiting the actin-related protein 2/3 complex in human non-small cell lung carcinoma.

The actin cytoskeleton is extremely dynamic and supports diverse cellular functions in many physiological and pathological processes, including tumorigenesis. However, the mechanisms that regulate the actin-related protein 2/3 (ARP2/3) complex and thereby promote actin polymerization and organization in cancer cells are not well-understood. We previously implicated the proline-rich 11 (PRR11) protein in lung cancer development. In this study, using immunofluorescence staining, actin polymerization assays, and siRNA-mediated gene silencing, we uncovered that cytoplasmic PRR11 is involved in F-actin polymerization and organization. We found that dysregulation of PRR11 expression results in F-actin rearrangement and nuclear instability in non-small cell lung cancer cells. Results from molecular mechanistic experiments indicated that PRR11 associates with and recruits the ARP2/3 complex, facilitates F-actin polymerization, and thereby disrupts the F-actin cytoskeleton, leading to abnormal nuclear lamina assembly and chromatin reorganization. Inhibition of the ARP2/3 complex activity abolished irregular F-actin polymerization, lamina assembly, and chromatin reorganization due to PRR11 overexpression. Notably, experiments with truncated PRR11 variants revealed that PRR11 regulates F-actin through different regions. We found that deletion of either the N or C terminus of PRR11 abrogates its effects on F-actin polymerization and nuclear instability and that deletion of amino acid residues 100-184 or 100-200 strongly induces an F-actin structure called the actin comet tail, not observed with WT PRR11. Our findings indicate that cytoplasmic PRR11 plays an essential role in regulating F-actin assembly and nuclear stability by recruiting the ARP2/3 complex in human non-small cell lung carcinoma cells.

DLX6-AS1/miR-204-5p/OCT1 positive feedback loop promotes tumor progression and epithelial-mesenchymal transition in gastric cancer.

BACKGROUND: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) participate in progression of gastric cancer (GC). Nevertheless, the function and expression level of DLX6-AS1 in GC remain unknown. METHODS: We explored the sequencing data of DLX6-AS1 downloaded from The Cancer Genome Atlas. The expression of DLX6-AS1, miR-204-5p and OCT1 in 56 GC patients and GC cell lines was quantified by qRT-PCR and western blotting. Furthermore, we performed in vitro functional assays to assess proliferation, invasion and migration of GC cells by knockdown of DLX6-AS1. The expression level of epithelial-mesenchymal transition (EMT)-related genes was also determined by qRT-PCR and western blotting. Actin remodeling was detected by F-actin phalloidin staining. The luciferase reporter assay and chromatin immunoprecipitation assay was utilized to confirm the bioinformatic prediction. The function of the DLX6-AS1/miR-204-5p/OCT1 axis in GC proliferation was clarified by rescue assays. RESULTS: We first demonstrated that DLX6-AS1 was upregulated in GC tissues and cell lines and was associated with T3/T4 invasion, distant metastasis and poor clinical prognosis. Further functional analysis showed that downregulation of DLX6-AS1 inhibited GC cell proliferation, migration, invasion and EMT in vitro. Mechanistic investigation indicated that DLX6-AS1 acted as a cancer-promoting competing endogenous RNA (ceRNA) by binding miR-204-5p and upregulating OCT1. Moreover, the transcription factor OCT1 was confirmed to enhance DLX6-AS1 expression by targeting the promoter region. CONCLUSIONS: This study revealed that OCT1-induced DLX6-AS1 promoted GC progression and the EMT via the miR-204-5p/OCT1 axis, suggesting that this lncRNA might be a promising prognostic biomarker and therapeutic target for GC.

SAMD14 promoter methylation is strongly associated with gene expression and poor prognosis in gastric cancer.

BACKGROUND: Gastric cancer (GC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related mortality. In recent years, SAMD14 has been studied in various malignant cancers; however, little is known about the exact mechanisms of SAMD14 involvement in carcinogenesis and malignant progression. METHODS: 60 paired GC-normal gastric tissues were evaluated for their SAMD14 mRNA expression in relation to SAMD14 gene promoter methylation. GC patient survival was assessed by Kaplan-Meier analyses and a Cox's proportional hazard model was employed for multivariate analyses. RESULTS: SAMD14 expression was significantly inversely correlated with the Borrmann type (P = 0.017), lymph node metastasis (P = 0.006) and tumor-node-metastasis (TNM) stage (P = 0.033). Methylation-specific PCR (MSP) revealed hyper-methylation of the SAMD14 promoter in 56.7% (34/60) of the primary GC tissues tested and in 10% (6/60) of matched non-malignant tissues. The SAMD14 promoter methylation status was also related to pathological differentiation, Borrmann type, TNM stage and lymph node metastasis. The results showed SAMD14 expression was significantly downregulated in Borrmann type, lymph node metastasis and TNM stage, which showed significantly higher methylation. SAMD14 promoter hyper-methylation was significantly associated with a poor prognosis and could serve as an independent marker for survival using multivariate Cox regression analysis. CONCLUSIONS: Our results indicated that promoter methylation was a key mechanism contributing to the downregulation of SAMD14 in GC. SAMD14 may be an epigenetically silenced tumor suppressor gene, and hyper-methylation of the SAMD14 promoter may serve as a biomarker to predict the clinical outcome of GC.

ZEB1-AS1 initiates a miRNA-mediated ceRNA network to facilitate gastric cancer progression.

BACKGROUND: Currently, cancer-related competing endogenous RNA (ceRNA) networks are attracting significant interest. As long noncoding RNA ZEB1-AS1 has been reported to function as an oncogene due to sponging microRNAs (miRNAs) in several cancers, we hypothesized that it could interact with specific miRNAs to form regulatory networks and facilitate the growth of gastric cancer (GC). METHODS: MiRNAs interacting with ZEB1-AS1 were screened for and selected by bioinformatics analysis. Overexpression or repression of ZEB1-AS1 was performed to determine whether it could regulate selected miRNAs. Quantitative real-time polymerase chain reactions (qPCR) validated the expression profiles of ZEB1-AS1 and miR-149-3p in GC cell lines and tissue. Statistical analysis determined the clinical significance of ZEB1-AS1 in relation to miR-149-3p. Cell counting, wound healing and transwell assays were performed to assess cell proliferation, migration and invasion. A luciferase reporter assay was utilized to confirm the putative miR-149-3p-binding sites in ZEB1-AS1. RESULTS: Briefly, bioinformatics analysis inferred that ZEB1-AS1 interacts with miR-204, miR-610, and miR-149. Gain- or loss-of function assays suggested that ZEB1-AS1 negatively regulates miR-149-3p, miR-204-5p and miR-610 in GC cells. Validated by qPCR, ZEB1-AS1 was up-regulated and miR-149-3p down-regulated in GC cells and tissue. Data analyses indicated that ZEB1-AS1 and miR-149-3p are associated with the independent diagnosis and prognosis of GC. Functional assays support the theory that miR-149-3p hinders GC proliferation, migration and invasion, whereas its overexpression abrogates the corresponding effects induced by ZEB1-AS1. Lastly, dissection of the molecular mechanisms involved indicated that ZEB1-AS1 can regulate GC partly via a ZEB1-AS1/miR-149-3p axis. CONCLUSIONS: ZEB1-AS1 can interact with specific miRNAs, forming a miRNA-mediated ceRNA network and promoting GC progress, partly through a ZEB1-AS1/miR-149-3p axis.

Correction to: ZEB1­AS1 initiates a miRNA­mediated ceRNA network to facilitate gastric cancer progression.

[This corrects the article DOI: 10.1186/s12935-019-0742-0.].

Downregulation of microRNA-376a in Gastric Cancer and Association with Poor Prognosis.

BACKGROUND/AIMS: MicroRNAs have a significant role in the tumorigenesis and progression of cancers, including gastric cancer (GC). Our study aimed to identify a novel biomarker to predict the prognosis of patients with GC. METHODS: The GC microarray dataset, GSE28700, was downloaded from the Gene Expression Omnibus (GEO) database and screened for differentially expressed miRNAs (DEMs). The downregulation of miR-376a expression was verified in GC cell lines and 82 paired GC tissues by performing RT-qPCR and the correlation between its expression and clinicopathological characteristics was also explored. The target genes of miR-376a were predicted using TargetScan7.1, miRDB, and DIANA website tools. A functional enrichment analysis was performed to explore the biological role of the common target genes. RESULTS: Bioinformatics analysis found that miR-376a was downregulated in GC tissues. Compared with the control group, RT-qPCR results showed that the expression of miR-376a in GC cell lines and tissues were also significantly decreased. The expression of miR-376a was statistically associated with T and N stage. Survival analysis with Kaplan-Meier showed that GC patients in the low expression group had a poorer prognosis than those in the high expression group (median survival of 26.4 and 46.9 months, respectively). Univariate and multivariate analysis demonstrated that low miR-376a expression was an independent prognostic marker for poor survival. Functional enrichment analysis indicated that the common targets genes were involved in cell-cell communication, VEGF and mTOR1-mediated signaling, and epithelial-to-mesenchymal transition (EMT). CONCLUSION: The results suggest that miR-376a could play an important role in the tumorigenesis and progression of GC and act as a novel therapeutic target and prognostic indicator in patients with GC.

miR-1236-3p inhibits invasion and metastasis in gastric cancer by targeting MTA2.

BACKGROUND: MicroRNAs deregulation are common in human tumor progression. miR-1236-3p has been reported to function as tumor suppressor microRNA in various malignancies. The aim of this study was to demonstrate the downregulated expression of miR-1236-3p in gastric cancer (GC) tissues and cell lines, and clarify its biological function in GC. METHODS: Real-time polymerase chain reaction was used to measure the mRNA level of miR-1236-3p in GC. Dual luciferase assay was used to demonstrate that MTA2 was one of the candidate target genes of miR-1236-3p. Western blots were utilized to detect the protein levels. Cell function assays were also performed to determine the function of miR-1236-3p in GC. RESULTS: miR-1236-3p expression, which was associated with lymph node metastasis, differentiation and clinical stage, was significantly reduced in GC tissues and cell lines. miR-1236-3p over-expression could inhibit GC cell proliferation, migration and invasion, and inhibition of miR-1236-3p expression had opposite effects. Furthermore, we demonstrated that MTA2 was a candidate target of miR-1236-3p, and miR-1236-3p over-expression significantly inhibited the process of epithelial-mesenchymal transition. We also found that miR-1236-3p could suppress the PI3K/Akt signaling pathway in GC cells. CONCLUSIONS: Our results suggest that miR-1236-3p functions as a tumor suppressor in GC and could be a promising therapeutic target for GC.

Up-regulation of CRKL by microRNA-335 methylation is associated with poor prognosis in gastric cancer.

BACKGROUND: MicroRNAs have been suggested to play a vital role in regulating carcinogenesis, tumor progression and invasion. MiR-335 is involved in suppressing metastasis and invasion in various human cancers. However, the mechanisms responsible for the aberrant expression of miR-335 in gastric cancer (GC) remain unknown. METHODS: Expression of miR-335 in four GC cell lines and 231 GC tissues was determined by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). DNA methylation status in the CpG islands upstream of miR-335 in GC cell lines and tissues was determined by methylation-specific PCR and bisulfite sequence-PCR. The effects of the demethylating agent 5-aza-2'-deoxycytidine on cell proliferation, apoptosis, cell cycle, migration, and invasion were investigated in GC cell lines. RESULTS: Cancer-specific methylation was detected in the upstream CpG-rich regions of miR-335, which dramatically silenced its transcriptional activity in GC cell lines and tissues. Low levels of miR-335 expression and high levels of miR-335 methylation in GC tissues were associated with poor clinical features and prognosis. Restoration of miR-335 expression in GC cells promoted cell apoptosis, inhibited tumor cell migration, invasion, and proliferation, and arrested the cell cycle at G0/G1 phase. Overexpression of miR-335 significantly reduced the activity of a luciferase reporter containing the 3' untranslated region of V-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL). CONCLUSIONS: MiR-335 functions as a tumor suppressor and may be silenced by promoter hypermethylation. It plays a role in inhibiting tumor cell migration, invasion, and proliferation, arresting the cell cycle at G0/G1 phase, and promoting apoptosis in GC cells through targeting CRKL.

The gene pair PRR11 and SKA2 shares a NF-Y-regulated bidirectional promoter and contributes to lung cancer development.

Head-to-head gene pairs represent a unique feature of gene organization in eukaryotes, accounting for >10% of genes in the human genome. Identification and functional analysis of such gene pairs is only in its infancy. Recently, we identified PRR11 as a novel cancer-related gene that is implicated in cell cycle and lung cancer. Here we demonstrate that PRR11 is oriented in a head-to-head configuration with its neighboring gene, SKA2. 5'-RACE assay revealed that the intergenic spacer region between the two genes is <500 bp. Serial luciferase reporter assays demonstrated that a minimal 80-bp intergenic region functions as a core bidirectional promoter to drive basal transcription in both the PRR11 and SKA2 orientations. EMSA and ChIP assays demonstrated that NF-Y binds to and directly transactivates the PRR11-SKA2 bidirectional promoter. SiRNA-mediated NF-Y depletion significantly downregulated PRR11 and SKA2 expression. Expression of both PRR11 and SKA2 was significantly upregulated in lung cancer. Expression of the two genes was highly correlated with each other and with NF-Y expression. Remarkably, high expression of both PRR11 and SKA2 was associated with poorer prognosis in lung cancer patients compared with high expression of one gene or low expression of both genes. Knockdown of PRR11 and/or SKA2 remarkably reduced cell proliferation, migration, and invasion in lung cancer cells. Thus, the PRR11-SKA2 bidirectional transcription unit, which is a novel direct target of NF-Y, is essential for the accelerated proliferation and motility of lung cancer cells and may represent a potential target in the diagnosis and/or treatment of human lung cancer.

Type D personality is associated with delaying patients to medical assessment and poor quality of life among rectal cancer survivors.

OBJECTIVE: The aim of this research was to explore quality of life (QoL), mental health status, type D personality, symptom duration, and emergency admissions of Chinese rectal cancer patients as well as the relationship between these factors. METHODS: Type D personality was measured with the 14-item Type D Personality Scale (DS14). Mental health status was measured with the Hospital Anxiety and Depression Scale (HADS). The QoL outcomes were assessed longitudinally using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires at the baseline and 6 months after diagnosis. RESULTS: Of the 852 survivors who responded (94 %), 187 (22 %) had a type D personality. The proportion of patients with duration of symptoms >1 month and being diagnosed after emergency admissions in type D group is significantly higher than that in non-type D group. At both of the time points, type D patients reported statistically significant lower scores on most of the functional scales, global health status/QoL scales, and worse symptom scores compared to patients without a type D personality. At the 6-month time point, a higher percentage of patients in the type D group demonstrated QoL deterioration. Clinically elevated levels of anxiety and depression were more prevalent in type D than in non-type D survivors. CONCLUSIONS: Type D personality was associated with poor QoL and mental health status among survivors of rectal cancer, even after adjustment for confounding background variables. Type D personality might be a general vulnerability factor to screen for subgroups at risk for longer symptom duration and emergency admissions in clinical practice.