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Purpose Referring to global cancer statistics, the incidence of gastric cancer (GC) was ranked sixth; however, detailed mechanisms underlying its development were not thoroughly investigated. Previous studies have reported that inhibition of ubiquitin-specific peptidase 8 (USP8) induced degradation of several receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), embryonic stem cells (ESCs), etc. Nevertheless, the regulation of HER-2 by USP8 and the molecular mechanisms controlling their role in the pathogenesis of GC remain unknown. Patients and methods A total of 69 patients with histologically confirmed GC were recruited to satisfy the purpose of this study. Initially, tumor samples and GC cell lines were used to detect USP8 and HER-2 levels. Next, MTT and colony formation assays were applied to analyze cell proliferation capability. Cell migration and invasion ability were examined by transwell assays. To examine related mRNA and protein expressions, Western blot assays and quantitative real-time PCR (qRT-PCR) were performed. Immunofluorescence was used to detect the effect of USP8 inhibitor on GC cells. Finally, in vivo experiments were used to examine the effect of USP8 inhibitor. Results Patients with USP8 high-expression tumors have shown worse overall survival while opposite results found in patients with low USP8 expressions. Regarding disease prognosis, patients with low expression of USP8 and HER-2 were performed better prognosis, whereas those with overexpression of USP8 and HER-2 shown poor prognosis. USP8 inhibitor significantly inhibited HER-2 positive cell NCI-N87 proliferation and metastasis. In addition, USP8 stabilizes HER-2, preventing it from ubiquitin proteasome-mediated degradation. In vivo studies confirmed that the USP8 inhibitor inhibited HER-2 positive cell NCI-N87 tumor growth. However, it did not affect the HER2-negative cell MGC-803. Careful investigation unraveled that the USP8 inhibitor significantly inhibited NCI-N87 cell proliferation and metastasis via phosphatidylinositol-3-kinases/protein-serine-threonine kinase (PI3K/AKT) pathway. Conclusion The USP8 inhibited HER-2 positive GC cell proliferation and migration in vivo and in vitro and probably served as a novel potential therapeutic biomarker for HER-2 positive GC.

Background Ubiquitin specific peptidase 8 (USP8) has been reported to induce the degradation of several receptor tyrosine kinases such as epidermal growth factor receptor (EGFR), among which human epidermal growth factor receptor-3 (HER-3) is one of them. However, the role and functional mechanisms of USP8 and HER-3 in gastric cancer (GC) remain unknown. Objective To explore the function and mechanism of USP8 and HER-3 in the progression of GC. Materials and methods Eighty-eight patients with histologically confirmed GC were recruited for this study. Tumor samples and GC cell lines were used to detect USP8 and HER-3 levels. MGC803 (HER-3 negative GC cell) was selected as the control group and NCI-N87, MKN-45 and AGS (HER-3 positive GC cells) as the experimental group. USP8i and si-RNA were then used to down-regulate USP8 in each group. Apoptosis and cell-cycle experiments were performed to detect the effects of USP8 on GC cells. Cytotoxicity Assay Kit (MTT) and colony formation assays were used to analyze cell proliferation. Cell migration and invasion ability were examined by wound healing. The expression of related mRNA and protein was detected by Western blot and quantitative real-time PCR (qRT-PCR). In vivo experiments were used to examine the effect of USP8 and HER-3. Results Patients with high expression of USP8 or HER-3 tumors alone died earlier than those with low expression and the patients with both USP8 and HER-3 high expression had a shorter overall survival than those with the opposite pattern (both USP8 and HER-3 low expression). Down-regulation of USP8 inhibited cell proliferation and cell metastasis and also reduced the HER-3 expression. We also observed that down-regulation of USP8 inhibited the proliferation of GC cells which highly expressed HER-3. Moreover, down-regulation of USP8 could promote the apoptosis of HER3-positive GC cells and inhibit the proliferation of them by affecting the cell-cycle. In vivo studies demonstrated that down-regulation of USP8 inhibited HER-3 positive tumors growth. Conclusion Down-regulation of USP8 inhibits HER-3 positive GC cells proliferation in vivo and in vitro, which indicate that USP8 represents a feasible choice as a therapeutic target for HER-3 positive GC cells.

This study investigated the role and action of the Salvador 1 protein (SAV1, also called WW45) in colorectal cancer (CRC). For this, CRC SW480 and HCT116 cells were infected with lentiviruses of SAV1 overexpression vector (lenti-SAV1) and SAV1 short hairpin RNA (sh-SAV1) to overexpress and silence SAV1 respectively, or transfected with microRNA-21 (miR-21) mimic to overexpress miR-21. Relative mRNA levels of SAV1 and relative miR-21 levels in CRC tissues or cells were detected. The effects of SAV1 and miR-21 on cell proliferation and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and annexin V – fluorescein isothiocyanate (FITC) – propidium iodide (PI) flow cytometry, respectively. Our results revealed that SAV1 was downregulated in CRC tissues compared with the adjacent noncancerous tissues. Furthermore, SAV1 overexpression inhibited proliferation and promoted apoptosis in SW480 and HCT116 cells, whereas knockdown of SAV1 exerted the opposite effect. Additionally, the tumorigenesis of SW480 cells in xenografted mice was significantly inhibited by SAV1 overexpression but promoted by SAV1 knockdown. MiR-21 levels significantly and negatively correlated with SAV1 expression in CRC tissues. More importantly, miR-21 overexpression significantly abolished the SAV1-mediated inhibition of proliferation and stimulation of apoptosis of SW480. In conclusion, SAV1 suppresses tumor growth in CRC and is regulated by miR-21.

Gastric cancer (GC) is the fifth most commonly diagnosed cancer and the third leading cause of cancer-related death in the world. Microbiota is believed to be associated with GC. Growing evidences showed Helicobacter pylori played a key role in GC development. However, little was known about the microbiota in gastric juices and tissues in GC patients, and thus it was difficult to understand other potential microbial causation for GC. Here, we collected the gastric juice and surgically removed gastric tissues from GC patients to give insight into GC microbiota. Most microbes identified in the gastric samples were opportunistic pathogens or resident flora of the human microbiota. Further network analyses identified five opportunistic pathogens as keystone species. H. pylori is the direct cause of GC, but other opportunistic microbes might also function in GC development. The microbiota in the gastric juice and gastric tissue of the GC patients were complex, and some dominant opportunistic pathogens contributed to the GC development. This study introduces microbiota in gastric juice, gastric normal tissue and gastric cancer tissue of GC patients, and highlights the potential keystone microbes functioned during GC development.

Gastrointestinal tumor (GIT) is a common malignant tumor of the digestive system, which seriously threatens people's health and life. With the deepening of the study on the mechanism of tumor immune escape, programmed death receptor ligand 1 (PD-L1) has been proved to interact with the tumor microenvironment to mediate tumor immune escape. PD-L1 inhibitor is a hot spot in tumor immunotherapy in recent years, which can restore the activity of T cells, enhance the body's ability of immune response, and ultimately enable the immune system to effectively identify and kill gastric cancer cells, then achieve long-term tumor remission in patients with GITs. At present, variety of PD-L1 inhibitors such as pembrolizumab, nivolumab and avelumab have been approved for the market, and they have achieved good results in clinical studies on the GIT. This paper reviews the progress of PD-1/PD-L1 immunotherapy in GITs which include gastric cancer, colon cancer and rectal cancer.

The epigenetic regulation of gene expression (via DNA methylation, histone modification and microRNA interference) contributes to a variety of diseases, particularly cancer. Protein deubiquitination serves a key role in the mechanism underlying histone modification, and consequently influences tumor development and progression. Improved characterization of the role of ubiquitinating enzymes has led to the identification of numerous deubiquitinating enzymes (DUBs) with various functions. Gastric cancer (GC) is a highly prevalent cancer type that exhibits a high mortality rate. Latest analysis about cancer patient revealed that GC is sixth deadliest cancer type, which frequently occur in male (7.2%) than female (4.1%). Complex associations between DUBs and GC progression have been revealed in multiple studies; however, the molecular mechanism underpinning the metastasis and recurrence of GC is yet to be elucidated. Generally, DUBs were upregulated in gastric cancer. The relation of DUBs and tumor size, classification and staging was observed in GC. Besides, 5-yar survival rate of patients with GC is effeccted by expression level of DUBs. Among the highly expressed DUBs, specifically six DUBs namely UCHs, USPs, OTUs, MJDs, JAMMs and MCPIPs effect on this survival rate. Consequently, the association between GC and DUBs has received increasing attention in recent years. Therefore, in the present review, literature investigating the association between DUBs and GC pathophysiology was analyzed and critically appraised.

A simple and safe triangle-valve technique (TVT) was applied in proximal gastrectomy (PG) in order to prevent postoperative gastric reflux among patients with adenocarcinoma of the esophagogastric junction (AEG). The clinical outcomes were evaluated in comparison to those of canonical total gastrectomy (TG). This retrospective study of 74 AEG patients compared two surgical procedures, PG-TVT (n=44) and TG (n=30), in terms of surgical outcomes, postoperative complications and nutritional status. The Reflux Disease Questionnaire (RDQ) was used to evaluate reflux esophagitis, and patients with an RDQ score of ≥12 points were diagnosed with gastroesophageal reflux disease (GERD). The mean operative time was significantly shorter in the PG-TVT group (242.6 min) compared with that in the TG group (288.1 min). The overall postoperative complication rate did not differ significantly between the PG-TVT and TG groups. All the patients were followed up for 6 months, and none developed cancer recurrence in distant organs, gastric remnant, or lymph nodes. The GERD incidence was similar between the PG-TVT and TG groups. The mean levels of total protein and albumin within 6 months were significantly higher in the PG-TVT group compared with those in the TG group after adjustingtthe time effect and the interaction of time and surgical methods. The level of total protein significantly increased within 6 months in the PG-TVT group, but decreased in the TG group. Therefore, PG-TVT has several advantages over TG for patients with AEG, including a shorter operative time and better postoperative nutritional status, whereas the incidence of GERD was found to be similar between the two techniques.

Objectives SAV1 is a human homologue of Salvador that contains two protein-protein interaction modules known as WW domains and acts as a scaffolding protein. SAV1 participates in the development of diverse types of cancer. We aimed to investigate the role of SAV1 in human colorectal cancer. Materials and methods Human colorectal cancer samples were used to study the expression of SAV1 and YAP. Loss-of-function and gain-of-function strategies were used to study the effects of SAV1 on colorectal cancer cell growth. Rapamycin was used to treat cells and mice to investigate the effect of mTOR signalling. Results SAV1 represses the development of colorectal cancer by inhibiting the Akt-mTOR signalling in a YAP-dependent manner. The mRNA and protein levels of SAV1 are down-regulated in human colorectal cancer tissues compared with adjacent non-cancer tissues. SAV1 knockdown promotes the growth of colorectal cancer cells in vitro and in vivo, whereas SAV1 overexpression leads to opposing results. SAV1 represses the activation of the Akt-mTOR signalling, and rapamycin treatment blunts the effects of SAV1 on in vitro and in vivo growth of colorectal cancer cells. Finally, we show that SAV1 promotes the phosphorylation and inactivation of YAP, which contributes to the effect of SAV1 on Akt-mTOR signalling pathway. Conclusions SAV1 is a repressor during the development of human colorectal cancer by inhibiting the YAP-Akt-mTOR signalling pathway.

Few epidemiological studies have examined the relationship between dietary fat, which may affect immune function and risk of Hodgkin lymphoma (HL). The aim of this study was to test the hypothesis that high dietary intake of fat and specific subtypes of fat is associated with the risk of HL among 486 HL cases and 630 population-based controls recruited between 1997 and 2000 in Connecticut and Massachusetts. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) stratified by age and gender. Among younger adults, HL risk was significantly and positively associated with higher intake of saturated fat [ORs for increasing quartiles = 1.3, 1.8, and 2.1; p trend = 0.04] and negatively associated with higher intake of monounsaturated fat [ORs for increasing quartiles = 0.5, 0.5, and 0.4; p trend = 0.03), after adjustment for potential confounders including lifestyle and other dietary factors. The associations with saturated fat (ORs for increasing quartile = 2.4, 3.2, and 4.4; p trend < 0.01] and monounsaturated fat (ORs for increasing quartile = 0.3, 0.6, and 0.3; p trend = 0.04) were most apparent in younger women, whereas there was no significant association between intake of total fat or any type of fat and risk of HL in older females or younger or older males. These findings show that the associations between dietary fat and risk of HL may vary by gender and age and require confirmation in other populations.

Descriptive studies have indicated a rising trend in Hodgkin's lymphoma (HL) incidence in young adults, especially females. Increasing evidence has suggested that some risk factors associated with HL may vary by age or gender. Recent studies have reported an increased risk of HL associated with increasing body mass index (BMI), but the results have been inconsistent. The objectives of this study were to examine whether the associations between measures of body size (height, weight, and BMI) and HL risk vary by age and/or gender.A population-based case-control study was conducted in Connecticut and Massachusetts. A total of 567 HL cases and 679 controls were recruited in 1997-2000. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs).Among younger women35 years old, being overweight (25-29.9 kg/m(2)) versus normal weight (18.5-24.9 kg/m(2)) was significantly associated with an increased risk of HL (OR = 2.1, 95 % CI = 1.1-4.0). The risk increased with increasing weight and BMI (p trends0.01). Among women ≥35 years old, by contrast, higher weight and BMI were associated with a reduced risk of HL (p trends0.01). Conversely, there was no significant association between BMI and risk of HL in younger or older males.These findings show that the associations between body size and risk of HL vary by gender and age, and require confirmation in other populations.

Accumulation of carotenoids in peel and pulp of the yellow-fleshed loquat ‘Zaozhong 6’ (ZZ6) and the white-fleshed loquat ‘Baiyu’ (BY) were tracked during different fruit development stages, and the expression of 15 carotenogenic genes were analyzed. During loquat fruit ripening the fresh weight content of β- carotene in peel and pulp of ZZ6 increased gradually and peaked at the fully ripe stage, reaching 68.53 µg⋅g −1 FW in the peel and 11.92 µg⋅g −1 FW in the pulp. In BY, the content of β -carotene in the peel increased and peaked at the fully ripe stage, reaching 38.89 µg⋅g −1 FW, while it decreased in the pulp from the original 0.47 µg⋅g −1 FW and reduced to 0.29 µg⋅g −1 FW. The content of β -cryptoxanthin in the peel and pulp of ZZ6 and BY both increased steadily, and peaked at the fully ripe stage; however, the content of lutein decreased in the peel of ZZ6 and increased in the pulp, but in BY, it dropped and then rose in the peel. There was no significant change of β -cryptoxanthin in the pulp of BY. After the breaker stage, the mRNA levels of phytoene synthase ( PSY ) and chromoplast-specific lycopene β -cyclase ( CYCB ) were higher in the peel, while CYCB and β -carotene hydroxylase ( BCH ) mRNAs were higher in the flesh of ZZ6, compared with BY. The results showed that the expression level of PSY , CYCB , and BCH appeared to cooperatively regulate the accumulation of carotenoids.