Search

A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10) plays a role in extracellular matrix and correlates with Weill-Marchesani syndrome. However, its role in gastric cancer remains unknown. Thus, we started this research to unveil the role of ADAMTS10 in gastric cancer (GC).The expression of ADAMTS10 in GC was analyzed by immunohistochemical staining and quantitative RT-PCR (qRT-PCR). The effects of ADAMTS10 inhibiting GC cell progression were conducted by functional experiments in vitro and in vivo. Flow cytometry was used to discover changing of cell cycle, apoptosis and ROS by ADAMTS10 in GC cell. Western blot was applied to identify targets of ADAMTS10. Western blot, qRT-PCR and flow cytometry were applied to discover the effect of ADAMT10 on THP1.ADAMTS10 expression was downregulated in GC tissue and patients with low ADAMTS10 levels had poorer overall survival. ADAMTS10 overexpression altered cell cycle, promoted apoptosis, and inhibited proliferation, migration, and invasion in vitro and in vivo. ADAMTS10 regulated TXNIP and ROS through the JAK/STAT/c-MYC pathway. Decreasing TXNIP and ROS reversed the inhibitory effect of ADAMTS10 on cell migration and invasion in vitro. ADAMTS10 secreted by GC cells was absorbed by THP1 and regulated TXNIP and ROS in THP1. ADAMTS10 secreted by GC cells inhibited macrophage M2 polarization.These results suggest that ADAMTS10 targets TXNIP and ROS via the JAK/STAT/c-MYC pathway and that may play important roles in GC progression and macrophage polarization which indicates that ADAMTS10 can be a potential survival marker for gastric cancer.

Purpose: A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) is involved in the angiogenesis and tumorigenesis of gastrointestinal cancer. However, the exact molecular and biological mechanisms of ADAMTS12 in gastric cancer (GC) remain unclear. This study aims to explore the exact underlying mechanisms of ADAMTS12 and provide a biomarker for prognosis and chemotherapy in GC. Methods: Gain- and loss-of-function assays were used to reveal the effect of ADAMTS12 on cell proliferation, migration, invasion, tube formation and chemoresistance in vitro and in vivo. IHC was used to analyze the expression and the correlation between ADAMTS12, VEGF and CD31 in gastric cancer tissues with or without neoadjuvant chemotheraphy. Results: ADAMTS12 promotes cell proliferation, angiogenesis and chemoresistance in vitro and in vivo. ADAMTS12 upregulates VEGF expression through ERK activation, which in turn, promoting angiogenesis and reducing sensitivity to oxaliplatin in GC. In GC tissues, ADAMTS12 was positively correlated with VEGF and microvessel density (MVD). Furthermore, patients with high ADAMTS12 level had poor overall survival (OS) and poor response to neoadjuvant chemotherapy. Conclusion: ADAMTS12 enhances chemoresistance to oxaliplatin in normoxic and hypoxic microenvironments via the MAPK/VEGF signaling pathway in GC. High ADAMTS12 levels have prognostic significance for poor survival, and indicator of vascular abnormality and chemoresistance in GC.

Supplementary Figure S2. DNA hypermethylation of the p75NGFR promoter analyzed in 29 cancer types from the TCGA data portal. The relative positions of 9 analyzed methylation probes are indicated within a schematic map of the human p75NGFR gene. The red-labeled one is the same probe with our methyaltion array chip.

Supplementary figure legends.

Supplementary Table S1-S4

The nerve growth factor receptor (NGFR/p75) is a potential tumor suppressor, but its role in colorectal cancer is unknown. Here, the hypermethylation status, biologic function, and clinical relevance were determined for p75NGFR in colorectal cancer. The methylation status and expression of p75NGFR were assessed in colorectal cancer cell lines and clinical tissues by bisulfite genomic sequencing (BGS), qRT-PCR, and immunoblot assay. Methylation of p75NGFR was frequently found in colorectal cancer, leading to its silencing or downregulation, and it was effectively restored by a demethylation agent. The overexpression of p75NGFR in multiple colorectal cancer cell model systems significantly inhibited cell proliferation (concomitant with G1-phase arrest), invasion, and colony formation and induced cell apoptosis. In contrast, p75NGFR knockdown significantly promoted proliferative and invasive phenotypes. Importantly, p75NGFR methylation was observed in the majority of primary colorectal cancer specimens and was associated with histologic grade and preoperative serum CA19-9 levels. Multivariate analysis indicated that patients who lack p75NGFR have reduced overall survival (64% vs. 75%, P = 0.028) and disease-free survival (61% vs. 72%, P = 0.034) compared with p75NGFR-positive patients. In conclusion, p75NGFR is predominantly silenced or downregulated in colorectal cancer, and its biologic activities are consistent with it being a relevant tumor suppressor.Implications: p75NGFR is a candidate tumor suppressor and has independent prognostic potential in colorectal cancer. Mol Cancer Res; 13(1); 107–19. ©2014 AACR.

To determine the morbidity, mortality, and pathologic outcomes of transanal total mesorectal resection (taTME) versus laparoscopic total mesorectal excision (laTME) among patients with rectal cancer with clinical stage I to III rectal cancer below the peritoneal reflection.Studies with sufficient numbers of patients allowing clinical acceptance of taTME for rectal cancer are lacking. Thus, we launched a randomized clinical trial to compare the safety and efficacy of taTME versus laTME.A randomized, open-label, phase 3, noninferiority trial was performed at 16 different hospitals in 10 Chinese provinces. The primary endpoints were 3-year disease-free survival and 5-year overall survival. The morbidity and mortality within 30 days after surgery, and pathologic outcomes were compared based on a modified intention-to-treat principle; this analysis was preplanned.Between April 13, 2016, and June 1, 2021, 1115 patients were randomized 1:1 to receive taTME or laTME. After exclusion of 26 cases, modified intention-to-treat set of taTME versus laTME groups included 544 versus 545 patients. There were no significant differences between taTME and laTME groups in intraoperative complications [26 (4.8%) vs 33 (6.1%); difference, -1.3%; 95% confidence interval (CI), -4.2% to 1.7%; P=0.42], postoperative morbidity [73 (13.4%) vs 66 (12.1%); difference, 1.2%; 95% CI, -2.8% to 5.2%; P=0.53), or mortality [1 (0.2%) vs 1 (0.2%)]. Successful resection occurred in 538 (98.9%) versus 538 (98.7%) patients in taTME versus laTME groups (difference, 0.2%; 95% CI, -1.9% to 2.2%; P0.99).Experienced surgeons can safely perform taTME in selected patients with rectal cancer.

Background Nutritional status and quality of life deteriorate significantly after total gastrectomy for patients with gastric cancer. The numerous types of reconstruction proposed by medical researchers around the world have limited effect. This prospective, randomized clinical trial compared functional jejunal interposition with Roux-en-Y anastomosis to identify the optimal reconstruction procedure. Methods This was a multi-center, prospective, randomized control trial. The enrolled patients were randomly assigned into the functional jejunal interposition group and the Roux-en-Y group. All patients were followed up at regular intervals after surgery. The endpoints were postoperative nutritional status, quality of life, and long-term postoperative complications. Results A total of 113 patients were enrolled from August 2012 to September 2017. Until March 2018, the median follow-up period was 18 months. At 12 months after surgery, food intake per meal (P = 0.021), Prognosis Nutritional Index (P = 0.015), weight loss (P = 0.019), and Gastrointestinal Symptom Rating Scale score (P = 0.015) of the functional jejunal interposition group were significantly worse than those of the Roux-en-Y group. There was no significant difference in operative time, intraoperative blood loss, perioperative complications, time of first flatus and defecation after surgery, postoperative plasma nutritional parameters, Visick score, Eastern Cooperative Group physical condition score, and survival rate. Conclusion For patients with long-term survival after total gastrectomy for gastric cancer, the Roux-en-Y anastomosis is a better choice compared with functional jejunal interposition.

We evaluated the functional outcomes and health-related quality of life (HRQoL) of 117 patients (who had had primary operations for oral and oropharyngeal squamous cell carcinoma) using the University of Washington Quality of Life Questionnaire version 4 (UW- QOL V4), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire version 3 (EORTC QLQ-C30 v3) and Head and Neck version 1 (EORTC HN35 v1). The patients were divided into groups according to the reconstruction techniques used: primary closure, submental island pedicled flap (SIPF), and radial forearm free flap (RFFF). Patients who had reconstruction with RFFF had better HRQoL as measured by swallowing, mastication, speaking, and overall score, than the primary closure group (p0.05). There was no significant difference (p0.05) between the RFFF and SIPF groups in overall QOL one year postoperatively. The HRQoL of the SIPF group was also better than that of the primary closure group in terms of mastication, speaking, and loss of appetite. Swallowing, mastication, and speaking are major factors that affect the HRQoL of patients one year after operation for oral and oropharyngeal cancer. Flap reconstruction can improve patients' QoL postoperatively. They can regain their ability to speak and swallow through training, and the importance of this issue must be addressed postoperatively.

Fertilizers and microbial communities that determine fertilizer efficiency are key to sustainable agricultural development. Sugarcane is an important sugar cash crop in China, and using bio-fertilizers is important for the sustainable development of China’s sugar industry. However, information on the effects of bio-fertilizers on sugarcane soil microbiota has rarely been studied. In this study, the effects of bio-fertilizer application on rhizosphere soil physicochemical indicators, microbial community composition, function, and network patterns of sugarcane were discussed using a high-throughput sequencing approach. The experimental design is as follows: CK: urea application (57 kg/ha), CF: compound fertilizer (450 kg/ha), BF1: bio-fertilizer (1500 kg/ha of bio-fertilizer + 57 kg/ha of urea), and BF2: bio-fertilizer (2250 kg/ha of bio-fertilizer + 57 kg/ha of urea). The results showed that the bio-fertilizer was effective in increasing sugarcane yield by 3–12% compared to the CF treatment group, while reducing soil acidification, changing the diversity of fungi and bacteria, and greatly altering the composition and structure of the inter-root microbial community. Variance partitioning canonical correspondence (VPA) analysis showed that soil physicochemical variables explained 80.09% and 73.31% of the variation in bacteria and fungi, respectively. Redundancy analysis and correlation heatmap showed that soil pH, total nitrogen, and available potassium were the main factors influencing bacterial community composition, while total soil phosphorus, available phosphorus, pH, and available nitrogen were the main drivers of fungal communities. Volcano plots showed that using bio-fertilizers contributed to the accumulation of more beneficial bacteria in the sugarcane rhizosphere level and the decline of pathogenic bacteria (e.g., Leifsonia), which may slow down or suppress the occurrence of diseases. Linear discriminant analysis (LDA) and effect size analysis (LEfSe) searched for biomarkers under different fertilizer treatments. Meanwhile, support vector machine (SVM) assessed the importance of the microbial genera contributing to the variability between fertilizers, of interest were the bacteria Anaerolineace, Vulgatibacter, and Paenibacillus and the fungi Cochliobolus, Sordariales, and Dothideomycetes between CF and BF2, compared to the other genera contributing to the variability. Network analysis (co-occurrence network) showed that the network structure of bio-fertilizers was closer to the network characteristics of healthy soils, indicating that bio-fertilizers can improve soil health to some extent, and therefore if bio-fertilizers can be used as an alternative to chemical fertilizers in the future alternative, it is important to achieve green soil development and improve the climate.

Background A disintegrin and metalloproteinase with thrombospondin motifs 16 (ADAMTS16) has been reported to be involved in the pathogenesis of solid cancers. However, its role in gastric cancer (GC) is unclear. In this study, the role of ADAMTS16 in gastric cancer was investigated.Methods The effects of ADAMTS16 on cell migration, invasion and proliferation were investigated by functional experiments in vivo and vitro. Targets of ADAMTS16 were identified using bioinformatics analysis co-immunoprecipitation, immunofluorescence and dual-luciferase reporter gene analysis assays. The expression of ADAMTS16 in GC was analyzed in public datasets. The expression of ADAMTS16 and its correlations with the clinical characteristics of GC were investigated by immunohistochemistry.Results Ectopic ADAMTS16 expression significantly promoted tumor cell migration, invasion, and growth. Bioinformatics analysis and western blotting showed that ADAMTS16 upregulated the IFI27 protein through the NF-κb pathway, which was confirmed by immunofluorescence and western blot. Dual-luciferase reporter gene analysis identified a binding site between P65 and IFI27 that may be directly involved in the transcriptional regulation of IFI27. IFI27 knockdown reversed the promoting effect of ADAMTS16 on cell invasion,migration and proliferation indicating that ADAMTS16 acts on GC cells by targeting the NF-κb/IFI27 axis. ADAMTS16 was associated with poor prognosis in clinical characteristics.Conclusions ADAMTS16 promotes cell migration, invasion and proliferation by targeting IFI27 through the NF-κB pathway and is a potential progressive and survival biomarker of GC.

A Disintegrin and Metalloproteinase with Thrombospondin motifs 19 (ADAMTS19) has been reported to participate in the pathogenesis of solid cancers. However, its role in gastric cancer (GC) remains undocumented. Using immunohistochemistry (IHC) staining and quantitative real-time polymerase chain reaction (qRT-PCR) on GC tissues and adjacent normal tissues, we found that ADAMTS19 was downregulated in GC tissues (IHC: p &lt, 0.001, qRT-PCR: p = 0.017). Further investigation revealed that ADAMTS19 correlated with distant metastasis (p = 0.008) and perineural invasion (p = 0.018) and that patients with low ADAMTS19 had worse overall survival (p = 0.021). Gain- and loss-of-function assays showed that ADAMTS19 suppressed cell migration and invasion in vitro. Using bioinformatics analysis and co-immunoprecipitation, immunofluorescence, and dual-luciferase reporter gene assays, we confirmed that ADAMTS19 binds with cytoplasm P65, decreasing the nucleus phosphorylation of P65, a crucial transcription factor in the nuclear factor kappa-B (NF-κB) pathway, thereby downregulating S100 calcium-binding protein A16 (S100A16) expression. S100A16 acted as the downstream of ADAMTS19, reversing the suppression of cell migration and invasion by ADAMTS19 in vitro. A combination of ADAMTS19 and S100A16 expression provided the optimal prognostic indicator for GC. Patients with ADAMTS19high-S100A16low had better overall survival than ADAMTS19low-S100A16high patients (p = 0.006). These results suggest that ADAMTS19 suppresses cell migration and invasion by targeting S100A16 via the NF-κB pathway and that ADAMTS19 and S100A16 are potential metastasis and survival biomarkers for GC.

Colorectal cancer (CRC) is currently the third leading cause of cancer-related deaths worldwide, and 5-fluorouracil (5-FU)-based chemotherapies serve as important adjuvant therapies before and after surgery for CRC. However, the efficacy of CRC chemotherapy is limited by chemoresistance, and therefore the discovery of novel markers to indicate chemosensitivity is essential. Nerve growth factor receptor (NGFR), a cell surface receptor, is involved in cell death and survival. Our previous study indicated that NGFR acts as a tumor suppressor, and high expression is associated with better outcomes in patients receiving 5-FU-based adjuvant chemotherapy after surgery. The aim of this study was to investigate the effect of NGFR on the chemotherapeutic response in CRC. Chemosensitivity was investigated using DLD1 and HCT8 cells after NGFR transfection. Apoptosis was investigated by flow cytometry. Autophagy was assessed using GFP-LC3B transient transfection. Gene expression was measured using an mRNA microarray. Beclin-1 and Bcl-2 protein expressions were assessed by western blot. NGFR and S100 calcium-binding protein A9 (S100A9) expressions in CRC patients were investigated by immunohistochemistry. The results showed that the half maximal inhibitory concentration of NGFR-transfected cells was lower than that of controls in DLD1 and HCT8 cells after 5-FU treatment, and cell viability was lower than in empty-vector cells. Tumor sizes were also smaller than in empty-vector cells in vivo. The percentages of apoptotic and autophagic cells were higher in NGFR-transfected cells. NGFR elevated the expression of S100A9 after 5-FU treatment. The combination of Bcl-2 and Beclin-1 was significantly suppressed by overexpressed NGFR. Five-year overall and disease-free survival in NGFR+/S100A9+ patients was better than in NGFR−/S100A9− patients. This study’s findings suggest that NGFR may serve as a marker predicting CRC patients’ chemosensitivity.

Fecal immunochemical test (FIT) is often used for preselection for colonoscopy, but FIT has nonoptimal sensitivity. Selection of study participant for colonoscopy based on the result of combining FIT with risk factors could improve the sensitivity of a screening program. We aimed to develop a risk prediction system of colorectal neoplasia among asymptomatic Chinese subjects. A total of 6265 asymptomatic participants with age between 50 and 70 years were invited to undergo colonoscopy screening. They were also asked to take FIT and complete a questionnaire for collecting information on risk factors. Independent risk factors were identified by binary logistic regression for colorectal neoplasia. A risk score model was developed by using the odds ratios of significant risk factors. The scoring system was divided into two groups of risk: negative risk and positive risk. The performance of the risk score model in terms of predicting colorectal neoplasia was evaluated. Of the 1786 colonoscopy screening participants, 1546 completed FIT and questionnaires. A total of 462 cases of neoplasia were detected. Based on the scoring stratification, 966 (62.5%) participants were in negative risk tier and 580 (37.5%) were in positive risk tier. The incidence of colorectal neoplasia in negative risk and positive risk groups was 18.4 and 49.0%, respectively. Risk stratification model has better ability to discriminate those with or without colorectal neoplasia than FIT-only model. Classification improved significantly with risk stratification-based screening (net reclassification improvement = 0.064, P = 0.032). Risk stratification system increases the predictive value of FIT-based screening and is useful for preselection for colonoscopy in colorectal cancer screening program.

ADAMTS5 has been reported to be involved in the progression of several human tumors. Nevertheless, the role of ADAMTS5 in gastric cancer (GC) remains poorly defined. ADAMTS5 expression levels were analyzed by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in GC cell lines and tissues, and the correlations between ADAMTS5 expression and clinicopathological features and survival were also examined. In vitro assays, including transwell assays, wound healing assays and cell adhesion assays, were employed to further explore the biological functions of ADAMTS5. A MAP kinase pathway microarray was used to identify the underlying mechanisms. The expression of ADAMTS5 and ETS1 and the microvessel density (MVD) were also analyzed using IHC to determine correlations with angiogenesis in GC. ADAMTS5 expression was downregulated in gastric cancer tissues. Low expression of ADAMTS5 was associated with gender, histological type, degree of differentiation, M stage, TNM stage and vascular invasion, and was also an independent indicator of a poor prognosis for patients with GC. ADAMTS5 overexpression markedly inhibited GC cell migration and invasion and enhanced cell adhesion to the extracellular matrix (ECM), whereas knockdown of ADAMTS5 exerted the opposite effects. Furthermore, the ADAMTS5 expression status was negatively correlated with ETS1 expression and MVD. ADAMTS5 is downregulated in GC and suppresses tumor metastasis and angiogenesis by inhibiting ETS1-mediated changes in MVD and potentially acts as a novel prognostic marker and a potential therapeutic target in human GC.

Nuclear receptor binding protein 1 (NRBP1) is a ubiquitously expressed and highly conserved pseudokinase that has important roles in cellular homoeostasis. Despite recent advances in understanding the biology of NRBP1, the role of NRBP1 and its underlying mechanism in colorectal cancer (CRC) have not been fully elucidated. In the present study, we observed that NRBP1 expression levels were significantly reduced in CRC tissues compared with corresponding adjacent normal tissues, and high NRBP1 expression correlated with better prognosis in CRC. Overexpression of NRBP1 inhibited CRC cell proliferation and promoted apoptosis in vitro and in vivo. In contrast, knockdown of NRBP1 expression increased cell proliferation and decreased the percentage of apoptotic cells. Moreover, overexpression of NRBP1 activated caspase-dependent intrinsic apoptosis. In addition, we further discovered that NRBP1 regulated the apoptotic pathway through interaction with JNK. Finally, NRBP1 overexpression led to attenuated CRC growth in a xenograft mouse model. Our study illustrates the suppressor role of NRBP1 in CRC and provides a potential therapeutic target.

Objective To explore the performance of a protocol combining fecal immunochemical test (FIT) and a high-risk factor questionnaire (HRFQ) for selecting patients requiring colonoscopy as part of a population-based colorectal cancer (CRC) screening program in China. Methods From 2015 to 2016, we conducted a CRC screening program for all residents aged 45 years or older in Tianhe District, Guangzhou City, China. Participants underwent an FIT and received an HRFQ as part of primary screening. Those with positive FIT and/or HRFQ results were considered to be at high risk and were recommended to undergo colonoscopy. Results A total of 10 074 subjects were recruited and enrolled in the screening program. In the enrolled population, 17.5% had positive FIT results and 19.4% had positive HRFQ results. Of those recommended to undergo diagnostic colonoscopy, 773 did so. The screening method’s overall positive predictive value (PPV) was 4.9% for non-adenomatous polyps, 11.4% for low-risk adenomas (LRAs), 15.9% for high-risk adenomas (HRAs) and 1.6% for CRC. The PPVs of positive FIT results for non-adenomatous polyps, LRAs, HRAs and CRC were 5.2%, 15.9%, 22.5% and 2.5%, respectively. The PPVs of positive HRFQ results for non-adenomatous polyps, LRA, HRA and CRC were 4.1%, 10.2%, 14.3% and 1.4%, respectively. The PPVs associated with combined positive FIT and HRFQ results for non-adenomatous polyps, LRAs, HRAs and CRC were 4.5%, 16.4%, 23.7% and 2.8%, respectively. Conclusion Our results suggest that this two-step CRC screening strategy, involving a combination of FIT and HRFQ followed by colonoscopy, is useful to identify early-stage CRC. The high detection rates and PPVs for CRC and adenomas encourage this strategy’s use in ongoing screening programs.

Gastric cancer (GC) is a prevalent upper gastrointestinal tumor characterized by high morbidity and mortality due to imperfect screening systems and the rapid development of resistance to 5‐fluorouracil (5‐FU). CDGSH iron sulfur domain 2 (CISD2) has been recently regarded as a candidate oncogene in several types of tumors. It is, therefore, necessary to investigate its biological function and clinical significance in gastric cancer. In this study, the down‐regulated expression level of CISD2 in GC compared with adjacent normal tissues was evaluated by quantitative RT‐PCR and Western blotting. An immunohistochemical analysis indicated that CISD2 expression in GC was significantly correlated with age (P = 0.002), Lauren's classification (P = 0.001), and differentiation (P = 0.049). Two cell lines, MKN1 and BGC823, were used to analyze the role of CISD2 in gastric carcinogenesis and response to 5‐FU through CCK‐8 assays, the RT‐CES system, Transwell assays, flow cytometry, and confocal fluorescence microscopy. The overexpression of CISD2 resulted in reduced cellular growth and proliferation, inhibition of metastatic ability, and increased apoptosis. 5‐FU treatment increased endogenous as well as exogenous overexpression of CISD2 in GC cells. Further investigation revealed that CISD2 enhanced sensitivity to 5‐FU via an increase in apoptosis and inhibition of protective autophagy through the activation of the AKT/mTOR pathway. In conclusion, CISD2 is down‐regulated in gastric cancer, and its effects on the inhibition of cellular proliferation, metastatic ability, and increased chemotherapy sensitivity are mediated by antagonism to 5‐FU‐induced autophagy through the AKT/mTOR pathway.

Long noncoding RNAs (lncRNAs) have been emerging as master regulators of tumor growth and metastasis, but the functions and underlying mechanisms of lncRNAs in colorectal cancer (CRC) still need to be clarified. Here, we found a novel lncRNA u50535, which was greatly overexpressed in CRC tissues and was associated with poor prognosis in CRC patients. Function studies showed that u50535 was an oncogene in CRC both in vitro and in vivo. In mechanism, through RNA sequencing and rescue assay, we found that u50535 activates CCL20 signaling to promote cell proliferation and migration in CRC. Taken together, these findings suggest that u50535 can promote CRC growth and metastasis and may serve as a potential biomarker in CRC.

A disintegrin and metalloprotease 8 (ADAM8) is involved in the tumorigenesis of several types of solid tumors. However, its exact role in gastric cancer (GC) remains unclear. The aim of this study was to evaluate the clinical significance of ADAM8 in GC and to explore its biological effects on gastric carcinogenesis. In this study, quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical staining analysis revealed that ADAM8 messenger RNA expression was significantly upregulated in GC tissues compared with noncancerous tissues (P = 0.004), and that positive ADAM8 expression is much more common in tumor tissues compared with normal tissues (P0.001) and is correlated with T stage (P = 0.036), N stage (P = 0.048), vessel invasion (P = 0.002), and a shorter patient overall survival (P = 0.024). In vitro assay indicated that ADAM8 overexpression promoted cell growth and increased migration and invasion abilities by decreasing the p-p38/p-extracellular regulated protein kinases (p-ERK) ratio. In conclusion, ADAM8 promotes GC cell proliferation and invasion, and its expression is positively correlated with poor survival, indicating that it might be a promising target in GC therapy.

Angiogenesis is an indispensable mechanism involved in both physiological processes and various pathological conditions, such as inflammation, aberrant wound healing, tumor progression, and metastasis. Among many angiogenic stimulators and inhibitors, vascular endothelial growth factor (VEGF) is regarded as one of the most important members of the signaling protein family involved in blood vessel formation and maturation. The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) proteins are a family of multifunctional proteinases. Such proteolytic enzymes are associated with various physiological processes, such as collagen maturation, organogenesis, angiogenesis, and reproduction. Importantly, deficiency or overexpression of certain ADAMTS proteinases has been shown to be directly involved in a number of serious diseases, including tumor progression and metastasis. This review explores in-depth the connections between ADAMTS proteinases as positive/negative mediators during angiogenesis and VEGF.

Beclin-1 is an autophagy gene. It promotes the formation of the autophagic vesicle as well as plays an essential role in guarding the cells against chromosomal instability. Overexpression of Beclin-1 has been reported to predict a favorable survival in various cancers. However, little is known about its prognostic significance in colorectal cancer.A total of three hundred and sixty-three (363) colorectal tissues from colorectal cancer (CRC) patients were collected. Tissue micro-arrays and immunohistochemistry were used to investigate the expression and prognostic significance of Beclin-1 in CRC. The associations among Beclin-1 expression, clinicopathological parameters and prognosis were evaluated.Beclin-1 had a higher expression in CRC tissues than in normal tissues. A high expression of Beclin-1 was positively correlated with gender (P=0.027), histological grade (P=0.003), pM status (P=0.003) and clinical stage (P=0.024). Patients with a high Beclin-1 expression, when compared to those with a lower expression had both a better overall survival (OS, P=0.006) and disease-free survival (DFS, P=0.008). In the pT3 subgroup, Beclin-1 was also found to be a good prognostic indicator (P0.05). Multivariate analysis showed a high expression of Beclin-1 was indeed a positive independent prognostic factor of OS and DFS for CRC patients (P0.05).Our results demonstrated that a high expression of Beclin-1 correlated with a better overall survival and disease-free survival, thus serving as a favorable independent prognostic marker in CRC.

The nerve growth factor receptor (NGFR/p75) is a potential tumor suppressor, but its role in colorectal cancer is unknown. Here, the hypermethylation status, biologic function, and clinical relevance were determined for p75NGFR in colorectal cancer. The methylation status and expression of p75NGFR were assessed in colorectal cancer cell lines and clinical tissues by bisulfite genomic sequencing (BGS), qRT-PCR, and immunoblot assay. Methylation of p75NGFR was frequently found in colorectal cancer, leading to its silencing or downregulation, and it was effectively restored by a demethylation agent. The overexpression of p75NGFR in multiple colorectal cancer cell model systems significantly inhibited cell proliferation (concomitant with G1-phase arrest), invasion, and colony formation and induced cell apoptosis. In contrast, p75NGFR knockdown significantly promoted proliferative and invasive phenotypes. Importantly, p75NGFR methylation was observed in the majority of primary colorectal cancer specimens and was associated with histologic grade and preoperative serum CA19-9 levels. Multivariate analysis indicated that patients who lack p75NGFR have reduced overall survival (64% vs. 75%, P = 0.028) and disease-free survival (61% vs. 72%, P = 0.034) compared with p75NGFR-positive patients. In conclusion, p75NGFR is predominantly silenced or downregulated in colorectal cancer, and its biologic activities are consistent with it being a relevant tumor suppressor. Implications: p75NGFR is a candidate tumor suppressor and has independent prognostic potential in colorectal cancer. Mol Cancer Res; 13(1); 107–19. ©2014 AACR.

A disintegrin and metalloprotease with motif 5(ADAMTS5) has been involved in colorectal cancer (CRC) with hypermethylation in the promoter. However, its role in CRC remains unclear. The aim of this study was to explore the clinical significance and biological effect of ADAMTS5 on colorectal carcinogenesis. Through MSP, qRT-PCR, WB and IHC analysis, followed by a variety of in vitro assays, we report the function of ADAMTS5 in CRC. ADAMTS5 was markedly hypermethylaed and downregulated in tumor tissues compared with non-tumor tissues (p

Radiation enteritis (RE) has emerged as a significant complication that can progress to severe gastrointestinal disease and the mechanisms underlying its genesis remain poorly understood. The aim of this study was to identify temporal changes in protein expression potentially associated with acute inflammation and to elucidate the mechanism underlying radiation enteritis genesis. Male Sprague–Dawley rats were irradiated in the abdomen with a single dose of 10 Gy to establish an in vivo model of acute radiation enteritis. Two-dimensional fluorescence difference gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight spectrometer (MALDI-TOF) tandem mass spectrometry, and peptide mass fingerprinting were used to determine differentially expressed proteins between normal and inflamed intestinal mucosa. Additionally, differentially expressed proteins were evaluated by KO Based Annotation System to find the biological functions associated with acute radiation enteritis. Intensity changes of 86 spots were detected with statistical significance (ratio ≥ 1.5 or ≤ 1.5, P

Background and Aim Although the effect of neoadjuvant chemotherapy in gastric cancer has been extensively studied, the data of survival benefit are still controversial. The purpose of this work was to assess the effectiveness of neoadjuvant chemotherapy followed by surgery in patients with gastric cancer. Methods We searched systematically electronic through the databases of PUBMED, EMBASE, China Biological Medicine, and China National Knowledge Infrastructure Whole Article for studies published from 1975. Two reviewers independently evaluated the relevant reports and searched manually reference from these reports for additional trials. Outcomes assessed by meta-analysis included overall survival rate, progression-free survival rate, R0 resection rate, downstaging effect, postoperative complications, and perioperative mortality. Results Six randomized, controlled trials with 781 patients were included in the meta-analysis. Odds ratio (95% confidence interval; P-value), expressed as neoadjuvant chemotherapy and surgery versus surgery alone, was 1.16 (0.85–1.58; P = 0.36) for overall survival, 1.24 (0.78–1.96; P = 0.36) for R0 resection, 1.25 (0.75–2.09; P = 0.39) for postoperative complications, and 3.60 (0.59–22.45; P = 0.17) for perioperative mortality. Conclusions Compared with surgery alone, neoadjuvant chemotherapy followed by surgery was not associated with a higher rate of overall survival or complete resection (R0 resection). It does not increase treatment-related morbidity and mortality. This meta-analysis did not demonstrate a survival benefit for the combination of neoadjuvant chemotherapy and surgery.

The aim of this study was to determine the clinicopathological characteristics and outcomes of Chinese colorectal cancer (CRC) patients aged 75 years and older undergoing potentially curative surgery.A total of 2,482 CRC patients at TNM stage I-III undergoing surgical treatment between 1995 and 2005 were evaluated, and patients were divided into a younger (75 years old) and an elderly (≥75 years) group.There were 2,482 CRC patients in this study, of which 2,194 (88.4 %) patients were in the younger group (mean age 57 years) and 288 (11.6 %) were in the elderly group (mean age 79 years). Significant differences were observed between the two groups with regard to the American Society of Anesthesiologists' score, tumor location, co-morbidities, emergency procedures, use of chemotherapy, proportion admitted to the ICU, length of ICU stay, causes of death, T/N stage and postoperative recurrence. The postoperative mortality increased from 4.8 % in the younger group to 8.3 % in the older group (p = 0.011). Although significant differences were found in the overall 5-year survival (73 vs. 56 %, p 0.0001) and disease-free 5-year survival (68 vs. 54 %, p 0.0001) between the two groups, the cancer-specific 5-year survival was similar (88 vs. 85 %, p = 0.089) in both groups.Although elderly CRC patients have unique clinicopathological features, a higher postoperative mortality and a worse overall and disease-free survival compared with younger patients, the cancer-specific survival at five years is similar between elderly and younger patients. Elderly patients benefit from radical surgery and have a good postoperative oncological outcome, irrespective of their age.

To evaluate the safety and efficacy of laparoscopy-assisted distal gastrectomy (LADG) in patients with early gastric cancer (EGC) to determine whether LADG is an acceptable alternative to open distal gastrectomy (ODG).LADG combined with less than D2 or D2 lymphadenectomy for EGC is still a controversial surgical intervention for its uncertain oncological safety and economic benefit. We conducted this systematic review and meta-analysis that included randomized control trials (RCTs) and non-RCTs of LADG versus ODG to evaluate whether the safety and efficacy of LADG in patients with EGC are equivalent to those of ODG.A comprehensive search of PubMed, EMBASE, Cochrane Library, and China Knowledge Resource Integrated Database was performed. Eligible trials published between January 1, 1994, and December 31, 2010, were included in the study. Data synthesis and statistical analysis were carried out by RevMan 5.0 software. The quality of evidence was assessed by GRADEpro 3.2.2.Twenty-two studies with 3411 participants were included in this study. The mean number of lymph nodes retrieved in LADG was close to that retrieved in ODG (in the less than D2 resection: weighted mean difference [WMD] = -1.79; 95% confidence interval [95% CI], -5.78 to 2.19; P = 0.38; heterogeneity: P0.00001, I = 98%; and in the D2 resection: WMD = -1.53; 95% CI, -3.56 to 0.51; P = 0.14; heterogeneity: P = 0.23, I = 26%). The overall postoperative morbidity was significantly less in LADG than in ODG (relative risk = 0.58; 95% CI, 0.46-0.74; P0.00001; heterogeneity: P = 0.94, I = 0%). LADG reduced the intraoperative blood loss, postoperative analgesic consumption, and hospital duration, without increasing the total hospitalization costs and cancer recurrence rate. The long-term survival rate of patients undergoing LADG was similar to that of patients undergoing ODG. However, LADG was still a technically dependent and time-consuming procedure. Conversion rate of LADG was 0% to 2.94%. The reported reasons for conversion were bleeding, adhesion, and safety resection margin requirement.: There were potential biases and significant heterogeneity in some clinical outcome measures in this study. Methodologically high-quality controlled clinical trials were sparse for this new surgical intervention. According to The Grading of Recommendations Assessment, Development and Evaluation approach, when assessing the safety and efficacy of LADG by comparing with those of ODG with the defined clinical outcomes in patients with EGC, the quality of the currently available clinical evidence was very low.LADG may be a technically feasible alternative for EGC when it is performed in experienced surgical centers in which patients undergoing LADG may benefit from the faster postoperative recovery. However, the currently available evidence cannot exclude the potential clinical benefits or harms, especially in the node-positive cases. Methodologically high-quality comparative studies are needed for further evaluation.

C-Jun plays important roles in the development of multiple cancers, but no well-designed association studies have been conducted to assess the roles of its genetic polymorphisms in cancer risk. In a cohort of 1016 pairs of colorectal cancer (CRC) patients and matched cancer-free controls, we investigated two genetic polymorphisms in the promoter regions of the c-Jun (rs4646999, -673CT and rs2760501, -1318TG) via the Taqman assay and evaluated the association between two polymorphisms and risk of CRC. We found that both the -1318G and -673C variant genotypes were associated with an increased risk of CRC [-1318TG: odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.04-1.54; -1318GG: OR = 1.63, 95% CI = 1.03-2.60; -673CT: OR = 1.60, 95% CI = 1.23-2.07; -673CC: OR = 1.80, 95% CI = 1.36-2.37]. Haplotype association analysis showed that compared with the carriers of -1318T-673T haplotype, carriers of the -1318T-673C, -1318G-673T, and -1318G-673C haplotypes all had a significantly increased risk of CRC (P0.05 for all). The combined genotypes incorporating both polymorphisms obtained a more significantly additive risk of CRC (one variant genotype: OR = 1.81, 95% CI = 1.30-2.51; two variant genotype: OR = 2.42, 95% CI = 1.70-3.44). Moreover, we found that the change of the -1318T to G allele interact with the -673T to C allele elevated the transcription activity of the c-Jun, and we confirmed the same trends by analyzing c-Jun protein expression in the CRC tissues from patients carrying different number of variant genotypes. This study suggests that -673CT and -1318TG genetic variants in c-Jun promoter regions contribute to an increased risk of CRC, possibly by elevating the transcription activity and protein expression levels that appeared to upregulate activity of c-Jun thus tumorigenesis.

Current neoadjuvant chemoradiotherapy had limited impact on distal metastasis and survival in locally advanced rectal cancer. Here, we investigated a new sandwich-like neoadjuvant regimen with bevacizumab. This was a single-arm, open-labeled, phase II trial. Patients with locally advanced rectal cancer received sandwich-like neoadjuvant therapy with bevacizumab (induction therapy with bevacizumab and FOLFOX, concurrent chemoradiotherapy with bevacizumab and consolidation chemotherapy with FOLFOX). Surgery was performed 4–6 weeks later. The primary endpoint of this study was pathologic complete response. Twenty-five eligible patients were included. All completed the neoadjuvant therapy protocol. During the course of neoadjuvant therapy, 3 patients (12 %) had grade 4 hematological toxicity events and 12 (48 %) had grade 3 non-hematological toxicity events. According to RECIST criteria, 18 patients (72 %) achieved partial response and the rest seven patients (28 %) remained stable disease. Two patients (8 %) refused the subsequent surgical therapy for personal reasons, and 23 patients (92 %) underwent operations finally. Nine (39.1 %, 95 % CI 18.0–57.5 %) of them achieved pathologic complete response. Five of them (21.7 %) had postoperative complications. After a median follow-up period of 25.3 (14.4–40.9) months, four patients developed disease progression and two died of cancer. The 3-year overall survival rate was 95 % (95 % CI 69.5–99.3 %), and the 3-year disease-free survival rate was 72.5 % (95 % CI 33.7–90.9 %). Sandwich-like neoadjuvant therapy with bevacizumab is safe and effective for locally advanced rectal cancer.

Purpose: The aim of present study was to investigate the methylation and expression status of spleen tyrosine kinase (SYK) in human hepatocellular carcinoma (HCC) and to evaluate this information for its ability to predict disease prognosis. E-cadherin and TIMP-3 methylation was also analyzed here as control because both were associated with poor prognosis in some types of tumors. Experimental Design: We analyzed the methylation status of SYK, E-cadherin, and TIMP-3 in 124 cases of HCC and assessed the correlation of such methylations with clinicopathologic variables and prognosis after tumor resection. Results: We found that SYK, E-cadherin, and TIMP-3 genes were methylated in 27%, 27%, and 42% of HCC neoplastic tissues, respectively. The loss of SYK mRNA or Syk protein expression was highly correlated with SYK gene methylation. The patients with methylated SYK in neoplastic tissues had a significantly lower overall survival rate after hepatectomy than those with unmethylated SYK. No significant difference in overall survival rates, however, was found between groups of patients with methylated and unmethylated E-cadherin or TIMP-3. Patients with negative Syk protein expression had a significantly lower overall survival rate than those with positive Syk protein expression. Multivariate analyses indicated that factors affecting overall survival were tumor-node-metastasis stage, Child-Pugh classification, SYK methylation, or Syk protein status. Conclusions: Our results indicate that SYK methylation and loss of Syk expression in HCC neoplastic tissues are independent biomarkers of poor patient outcome and that determination of SYK methylation or Syk expression status may offer guidance for selecting appropriate treatments.

Aim: To investigate the risk factors of gastric remnant cancer. Methods: A search on PubMed, Embase, ISI Web of SCIENCE, Cochrane Library, CNKI, and Wanfang was performed to identify relevant literature published from January 1990 to May 2014. The effect of gastric remnant cancer was estimated by risk ratio (RRs) with 95% confidence intervals (CIs) for each study using a fixed effects or random effects model. Results: 28 studies with a total of 1132 patients met the inclusion criteria in our study. The risk for gastric remnant cancer was positively associated with a male gender, an initial ulcerative disease, a previous Billroth II anastomosis. Gastric remnant cancer was also more likely to be located at the site of initial anastomosis and was associated with a poorly differentiated and/or undifferentiated histology. However no significance was observed between the TNM stage and the gastric remnant cancer. Conclusion: Meta-analysis found that gastric remnant cancer is associated with gender, reason for initial surgery, type of initial surgery performed, location, histology.

One characteristic of the erythroid terminal differentiation is hemoglobin expression and enucleation. In the present study, by using real-time cultured Friend Virus Anemia-inducing (FVA) cells, scanning electron microscopy (SEM), immunofluorescence combined with laser scanning confocal microscopy (LSCM), the FVA cells induced by Erythropoietin (EPO) for were used for: 1) to study the shape and proportion of cells at different differentiating stages, enucleation process, the formation of blood islands, and engulfment of nuclei by macrophages in real time, 2) to quantitatively analyze erythroid cell surface markers including CD71 and Ter119, and cytoskeletal-associated proteins (stathmin, septin8 and RBBP4). The results of real-time monitoring of enucleation indicated that it took about 7 to 8 hours to extrude the nuclei from karyopyknosis (polychromatic erythroblasts). It further showed that the macrophages engulfed the expelled erythroid nuclei. SEM showed a variety of shapes of the nascent reticulocytes. In the process of erythroid differentiation, expressiosn of both the transferring receptors CD71 and Ter119 were higher than that of adult blood cells, whereas, cytoskeletal-associated proteins (stathmin, septin8 and RBBP4) decreased gradually. Therefore, systematic observation of the process of differentiation and enucleation will provide a deeper understanding of cellular and molecular mechanisms for erythroid differentiation and carcinogenesis.

Background: Classified as “diffuse” by the Lauren’s classification gastric signet ring cell carcinoma is an adenocarcinoma with distinct features which separates it from other types of gastric cancer. Affecting mainly young female patients, gastric SRC is mainly due to the loss of E-cadherin and CDH1+. In this review we look into the pathogenesis, clinical features, diagnosis, treatment, and prognosis of gastric SRC. Materials and Methods: We reviewed the literature published until September 2014 to identify studies of gastric SRC. Studies were identified by using the Medline and PubMed databases using the terms “gastric signet ring cell carcinoma”, “gastric signet ring cell cancer”, “signet ring cell cancer”, “signet ring cell carcinoma”. Researches on esophageal SRC, intestinal SRC were excluded in our study. Results: A down-regulation of epithelial cadherin is essential for the initiation, and progression of gastric signet ring cell cancer cells. Once gastric cells lose E-cadherin, they have an increase in motility due to epithelial-mesenchymal transition. A strong correlation in the mutation of Snail, Slug, and Twist as well as an activation of the phosphatidylinositol 3 kinase (PI3K)/AKT axis, Wnt/β-catenin signaling pathway, and transforming growth factor β have been found to be associated with the pathogenesis of gastric signet ring cell cancer. Diagnosis relies mainly on histological findings. While surgical treatment includes resection and lymphadenectomy with retrieval of at least 15 lymph nodes, few patients respond well to chemotherapeutic regimens. Conclusion: Despite recent advances, more patients are being diagnosed with advanced gastric SRC. Understanding the pathogenenis of gastric signet ring cell cancer is critical in the treatment and improving the prognosis of patients.