Decrease in GPSM2 mediated by the natural product luteolin contributes to colon adenocarcinoma treatment and increases the sensitivity to fluorouracil.

Luteolin, a monomeric substance, is a natural product of the Brucea javanica (BJ) plant. Brucea javanica oil emulsion injection (BJOEI) is a proprietary Chinese medicine purified from BJ that is widely used clinically as an anti-tumor treatment. Although a growing body of research suggests that luteolin and BJOEI have anti-tumor effects, the molecular mechanism of action has not been fully elucidated. In this study, through molecular docking technology, we found that luteolin can interact directly with GPSM2 and regulate the FoxO signaling pathway through GPSM2. In addition, the inhibitory effect of luteolin on colon adenocarcinoma (COAD) cells was found to be offset by knockdown of GPSM2. In contrast, the anti-proliferative effects of luteolin could be notably reversed by overexpression of GPSM2. The results reveal that GPSM2 is crucial in luteolin-mediated anti-proliferative effects. The mediation of anti-proliferative effects by GPSM2 has also been indirectly demonstrated in RKO and SW480 xenograft mice models. In addition, we verified that BJOEI inhibits the progression of COAD by mediating GPSM2 and regulating the FoxO signaling pathway. We also found that BJOEI achieved a better anti-tumor effect when combined with fluorouracil injection. Collectively, our data show that the anti-tumor effects of BJOEI and luteolin on COAD are GPSM2-dependent and downregulating the expression of GPSM2 to regulate the FoxO signaling pathway may be an effective way to treat COAD.

Mercury contamination is an invisible threat to declining migratory shorebirds along the East Asian-Australasian Flyway.

Exposure to pollutants is a potentially crucial but overlooked driver of population declines in shorebirds along the East Asian-Australasian Flyway. We combined knowledge of moult strategy and life history with a standardised sampling protocol to assess mercury (Hg) contamination in 984 individuals across 33 migratory shorebird species on an intercontinental scale. Over one-third of the samples exceeded toxicity benchmarks. Feather Hg was best explained by moulting region, while habitat preference (coastal obligate vs. non-coastal obligate), the proportion of invertebrates in the diet and foraging stratum (foraging mostly on the surface vs. at depth) also contributed, but were less pronounced. Feather Hg was substantially higher in South China (Mai Po and Leizhou), Australia and the Yellow Sea than in temperate and Arctic breeding ranges. Non-coastal obligate species (Tringa genus) frequently encountered in freshwater habitats were at the highest risk. It is important to continue and expand biomonitoring research to assess how other pollutants might impact shorebirds.

Short-term mercury exposure disrupts muscular and hepatic lipid metabolism in a migrant songbird.

Methylmercury (MeHg) is a global pollutant that can cause metabolic disruptions in animals and thereby potentially compromise the energetic capacity of birds for long-distance migration, but its effects on avian lipid metabolism pathways that support endurance flight and stopover refueling have never been studied. We tested the effects of short-term (14-d), environmentally relevant (0.5 ppm) dietary MeHg exposure on lipid metabolism markers in the pectoralis and livers of yellow-rumped warblers (Setophaga coronata) that were found in a previous study to have poorer flight endurance in a wind tunnel than untreated conspecifics. Compared to controls, MeHg-exposed birds displayed lower muscle aerobic and fatty acid oxidation capacity, but similar muscle glycolytic capacity, fatty acid transporter expression, and PPAR expression. Livers of exposed birds indicated elevated energy costs, lower fatty acid uptake capacity, and lower PPAR-γ expression. The lower muscle oxidative enzyme capacity of exposed birds likely contributed to their weaker endurance in the prior study, while the metabolic changes observed in the liver have potential to inhibit lipogenesis and stopover refueling. Our findings provide concerning evidence that fatty acid catabolism, synthesis, and storage pathways in birds can be dysregulated by only brief exposure to MeHg, with potentially significant consequences for migratory performance.

Review of contaminant levels and effects in shorebirds: Knowledge gaps and conservation priorities.

Environmental pollution has emerged as a major threat to bird populations. Many shorebird populations are declining, although contamination has been documented in some shorebirds, evidence of negative impacts is sparse and this important topic remains understudied. To guide future research and develop effective conservation strategies, we carried out a comprehensive review of environmental pollutants and their consequences on shorebirds. In total, we found 93 relevant articles which examined pollutant contamination in ~37% (79 of 215) of all shorebird species, mostly from the Charadriidae and Scolopacidae families. Studies were geographically biased: the majority were conducted in American flyways, while only 1 was found from Australasia and few were conducted in Asian flyways. The main geographic gap for research includes East Africa, South Asia and Siberian Arctic. The most well-documented pollutants included mercury (Hg, 37 studies), cadmium (33), and lead (Pb, 28); less well studied pollutants were barium (1), calcium (1), strontium (1), dicofols (1), and other newly emerging contaminants, such as plastic debris/microplastics (4) and antibiotics resistance (2). Several pollutants have caused considerable concerns in shorebirds, including embryotoxicity caused by PCBs at non-optimum temperature (laboratory experiments); reduced reproduction performance linked to maternal Hg and paternal Pb (field evidence); and reduced refueling and flight performance related to oil contamination (both field and laboratory evidence). Our results confirm that an in-depth understanding of the local, regional and global factors that influence population trends of shorebirds in light of increasing pollution threats is essential for accurate and effective management and conservation strategies.

Correction: Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers.

[This corrects the article DOI: 10.18632/oncotarget.3253.].

Mercury distribution in the East Himalayas: Elevational patterns in soils and non-volant small mammals.

Mercury (Hg), as a global pollutant, its contamination has been documented in environmental compartments of the Himalayan region. However, little research exists regarding to Hg accumulation in terrestrial wildlife, as well as its driving factors. In this study, surface soil and small mammals were collected in the Lebu Valley, East Himalayas of China, in order to measure the uptake of the long-distance transported Hg along an elevational gradient approximately from 2300 to 5000 m a.s.l. The soil Hg concentrations were measured and predicted mostly by vegetation type as well as soil organic matter, while the Hg in hair of small mammals (Muridae and Cricetidae) showed deeply influenced by soil Hg. Notably, combined with the field survey data, soil and hair Hg were both enhanced in low and mid-elevations, which overlapped the distribution ranges of a majority of mammals. Overall, this indicates that Hg contamination in low- and mid-elevations poses a potential threat to the top predators that consuming small mammals directly or indirectly. Furthermore, our data advances the understanding of Hg dynamics in remote, high mountain ecosystems and provides baseline data for biomonitoring for reduction of Hg emission globally.

Bufalin inhibits peritoneal dissemination of gastric cancer through endothelial nitric oxide synthase-mitogen-activated protein kinases signaling pathway.

Peritoneal dissemination threatens the survival of patients with gastric cancer (GC). Bufalin is an extract of traditional Chinese medicine, which has been proved to have anticancer effect. The target of bufalin in suppressing gastric cancer peritoneal dissemination (GCPD) and the underlying mechanism are still unclear. In this research, GC cell line MGC-803 and high-potential peritoneal dissemination cell line MKN-45P were treated with bufalin or L-NAME. Malignant biological behavior and protein level of GC cell lines were detected with MTT, wound healing, transwell, adhesion, and western blotting. Bioinformatics analysis and patient tissues were used to verify the role of endothelial nitric oxide synthase (NOS3) in GC. Mice model was used to assess the effect of bufalin and role of NOS3 in vivo. We found that bufalin inhibited the proliferation, invasion, and migration in GC cell lines. NOS3, which was an independent prognostic factor of GC patients, was predicted to be a potential target of bufalin. Further experiments proved that bufalin reduced the phosphorylation of NOS3, thereby inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, and ultimately suppressed GCPD by inhibiting EMT process. In conclusion, NOS3 was a potential therapeutic target and prognostic biomarker of GC. Bufalin could suppress GCPD through NOS3-MAPK signaling pathway, which provided more evidence support for intraperitoneal perfusion of bufalin to treat GCPD.

Pan-Cancer Analysis of NOS3 Identifies Its Expression and Clinical Relevance in Gastric Cancer.

Background: NOS3 (endothelial NOS, eNOS) is a member of the nitric oxide synthase (NOS) enzyme family, mainly participating in nitric oxide (NO) generation. NOS3 has been reported to inhibit apoptosis and promote angiogenesis, proliferation, and invasiveness. However, the expression pattern of NOS3 and its diagnostic and prognostic potential has not been investigated in a pan-cancer perspective. Methods: Data from the Genotype-Tissue Expression (GTEx), the Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE), and the Cancer Therapeutics Response Portal (CTRP) were employed and NOS3 expression was comprehensively analyzed in normal tissues, cancer tissues, and cell lines. Immunohistochemical staining of tissue sections were used to validate the prognostic role of NOS3 in gastric cancer patients. GSVA and GSEA analyses were performed to investigate signaling pathways related to NOS3 expression. Results: In normal tissues, NOS3 was expressed highest in the spleen and lowest in the blood. NOS3 expression was increased in stomach adenocarcinoma (STAD) and significantly associated with poor prognosis of patients. Immunohistochemical staining validated that NOS3 was an independent prognostic factor of gastric cancer. Several canonical cancer-related pathways were found to be correlated with NOS3 expression in STAD. The expression of NOS3 was related to the response to QS-11 and brivinib in STAD. Conclusions: NOS3 was an independent prognostic factor for patients with STAD. Increased expression of NOS3 influenced occurrence and development of STAD through several canonical cancer-related pathways. Drug response analysis reported drugs to suppress NOS3. NOS3 might be a novel target for gastric cancer treatment.

Inferring spatial patterns of mercury exposure in migratory boreal songbirds: Combining feather mercury and stable isotope (δ2H) measurements.

Migratory songbirds breeding in the Canadian Boreal forest are exposed to mercury (Hg), a potent neurotoxin that impairs avian health, however, the degree of exposure depends on many factors. As breeding grounds are geographically remote and vast, the measurement of Hg in individual birds is impractical particularly at large spatial scales. Here, we present a Canada-wide dataset of nearly 2000 migratory songbirds that were used to assess summer Hg exposure of 15 songbird species sampled during fall migration. We measured Hg concentrations in tail feathers and related those to dietary guild, geographic capture location, age, sex and probable breeding ground locations using feather δ2H. Overall mean (±SE) feather Hg concentration was 1.49 ± 0.03 µg/g (N = 1946): however, a clear geographic gradient in feather Hg concentrations emerged being highest in East and lowest in West. Dietary guild was the next strongest predictor of feather Hg with insectivorous songbirds in Eastern Canada at particular risk due to Hg exposure on summer breeding grounds. This broad-scale assessment of Hg exposure in migratory songbirds in Canada can be used to guide future studies on finer-scale determinants of Hg exposure in birds.

Breast cancer populations may have an increased prevalence of thyroglobulin antibody and thyroid peroxidase antibody: a systematic review and meta-analysis.

PURPOSE: Thyroid autoimmunity might be in relation to other autoimmune endocrine disease or non-endocrine disorders and there are innate and adaptive immune cells in breast cancer. Because autoimmune factors are common characteristics of both thyroid autoimmunity and breast cancer, these two types of diseases may occur concurrently in certain patients. The chief goal of this meta-analysis is to perform a combined analysis of the raw data from all included studies, and thereby obtain a reliable conclusion concerning whether TgAb or TPOAb positivity and breast cancer are indeed correlated. METHODS: To determine whether a correlation exists between TgAb or TPOAb positivity and breast cancer, this study performed a review of the literature that began by searching for articles in Chinese or English from the Medline, Embase, Web of Science core, Wanfang, Weipu and SinoMed databases, published during the time span extending from January 1980 to December 2017. On the basis of these raw data, we calculated odds ratio (OR) values, 95% confidence interval (CI) values, and P values. RESULTS: A total of 11 studies were included in this study. By combining the raw data from the retrieved studies, we were able to perform a meta-analysis. The results of this meta-analysis support the hypothesis that patients with breast cancer have a higher TgAb or TPOAb positive rate than the non-breast disease control group (TgAb: OR = 2.71, 95% CI = 1.81-4.05, P < 0.001; TPOAb: OR = 2.86, 95% CI = 2.17-3.77, P < 0.001, respectively). Testing for publication bias indicated that no significant publication bias was present in this meta-analysis, and sensitivity analysis indicated that the results of analysis were stable and reliable. CONCLUSIONS: The results of this meta-analysis suggest strongly that, the TgAb or TPOAb positive rate among patients with breast cancer should be higher than among the non-breast disease control group.

Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma.

PURPOSE: The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown. METHODS: Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both in vitro and in vivo xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays. RESULTS: We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling. CONCLUSIONS: Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.

ß-Elemene inhibits the metastasis of multidrug-resistant gastric cancer cells through miR-1323/Cbl-b/EGFR pathway.

BACKGROUND: ß-Elemene is a natural agent extracted from the traditional Chinese herbal medicine Curcuma wenyujin that is a promising novel plant-derived drug with broad-spectrum anticancer activity. Our previous study identified an enhanced capacity for metastasis in multidrug resistant (MDR) gastric cancer and breast cancer cells. However, the anti-metastatic effects of ß-Elemene on MDR cancer cells remain unknown. PURPOSE: In this study, we posit the hypothesis that ß-elemene possesses antimetastatic effects on MDR cancer cells. METHODS: Cell viability assay was used to assess the resistance of SGC7901/ADR cells and the cytotoxic effects of ß-Elemene. Wound healing, transwell assay and lung metastatic mice model were used to the anti-metastasis effects of ß-Elemene. MicroRNA microarray analysis was used to explore potential regulated miRNAs. Luciferase reporter assay was used to identify the direct target. Human MMP antibody array, western blot, immunoprecipitation, qRT-PCR analyses and immunohistochemistry were conducted to investigate the underlying anti-metastasis mechanism of ß-Elemene. RESULTS: In this study, we found that ß-Elemene significantly inhibited the metastatic capacity of MDR gastric cells in vivo and in vitro. Mechanistically, we found that ß-Elemene regulated MMP-2/9 expression and reversed epithelial-mesenchymal transition. Further studies showed that ß-Elemene upregulated Cbl-b expression, resulting in inhibition of the EGFR-ERK/AKT pathways, which regulate MMP-2/9. Additionally, we confirmed that ß-Elemene upregulated Cbl-b by inhibiting miR-1323 expression. Finally, we found that numbers of metastatic tumor nodules were significantly decreased in the lungs of nude mice after ß-Elemene treatment. CONCLUSION: Our results suggested that ß-Elemene inhibits the metastasis of MDR gastric cancer cells by modulating the miR-1323/Cbl-b/EGFR signaling axis.

Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF-ß1/Smad signaling pathway.

Mesenchymal glioblastoma (GBM) is the most aggressive subtype of GBM. Our previous study found that neurotrophic factor prosaposin (PSAP) is highly expressed and secreted in glioma and can promote the growth of glioma. The role of PSAP in mesenchymal GBM is still unclear. In this study, bioinformatic analysis, western blotting and RT-qPCR were used to detect the expression of PSAP in different GBM subtypes. Human glioma cell lines and patient-derived glioma stem cells were studied in vitro and in vivo, revealing that mesenchymal GBM expressed and secreted the highest level of PSAP among four subtypes of GBM, and PSAP could promote GBM invasion and epithelial-mesenchymal transition (EMT)-like processes in vivo and in vitro. Bioinformatic analysis and western blotting showed that PSAP mainly played a regulatory role in GBM invasion and EMT-like processes via the TGF-ß1/Smad signaling pathway. In conclusion, the overexpression and secretion of PSAP may be an important factor causing the high invasiveness of mesenchymal GBM. PSAP is therefore a potential target for the treatment of mesenchymal GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Role of abnormal microRNA expression in Helicobacter pylori associated gastric cancer.

Epidemiological studies have shown that Helicobacter pylori (HP) infection is a risk factor for gastric cancer (GC). HP infection may induce the release of pro-inflammatory mediators, and abnormally increase the level of reactive oxygen species (ROS), nitric oxide (NO), and cytokines in mucosal epithelial cells of the stomach. However, the specific mechanism underlying the pathogenesis of HP-associated GC is still poorly understood. Recent studies have revealed that abnormal microRNA expression may affect the proliferation, differentiation, and apoptosis of mucosal epithelial cells of the stomach to further influence GC occurrence, development, and metastasis. Herein, we summarize the role of abnormal microRNAs in the regulation of HP-associated GC progression. Abnormal microRNA expression in HP-positive GC may be a biomarker for GC diagnosis, occurrence, and development as well as its targeted treatment and prognosis.

Prosaposin promotes the proliferation and tumorigenesis of glioma through toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway.

BACKGROUND: As a neurotrophic factor, prosaposin (PSAP) can exert neuroprotective and neurotrophic effects. It is involved in the occurrence and development of prostate and breast cancer. However, there is no research about the role of PSAP in glioma. METHODS: The PSAP overexpressed or silenced glioma cells or glioma stem cells were established based on Lentiviral vector transfection. Cell viability assay, Edu assay, neurosphere formation assay and xenograft experiments were used to detect the proliferative ability. Western blot, Elisa and luciferase reporter assays were used to detect the possible mechanism. FINDINGS: Our study firstly found that PSAP was highly expressed and secreted in clinical glioma specimens, glioma stem cells, and glioma cell lines. It was associated with poor prognosis. We found that PSAP significantly promoted the proliferation of glioma stem cells and cell lines. Moreover, PSAP promoted tumorigenesis in subcutaneous and orthotopic models of this disease. Furthermore, GSEA and KEGG analysis predicted that PSAP acts through the TLR4 and NF-κB signaling pathways, which was confirmed by western blot, immunoprecipitation, immunofluorescence, and use of the TLR4-specific inhibitor TAK-242. INTERPRETATION: The findings of this study suggest that PSAP can promote glioma cell proliferation via the TLR4/NF-κB signaling pathway and may be an important target for glioma treatment. FUND: This work was funded by National Natural Science Foundation of China (Nos. 81101917, 81270036, 81201802, 81673025), Program for Liaoning Excellent Talents in University (No. LR2014023), and Liaoning Province Natural Science Foundation (Nos. 20170541022, 20172250290). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

Relationship between GSTP1 rs1695 gene polymorphism and myelosuppression induced by platinum-based drugs: a meta-analysis.

Although many previous studies have reported the relationship between GSTP1 rs1695 gene polymorphism and myelosuppression induced by platinum-based drugs, the conclusions are not consistent. The aim of the study is to evaluate the association between granulocytopenia and thrombocytopenia induced by platinum-based drugs and GSTP1 rs1695 gene polymorphism by meta-analysis. A literature search was performed using the Pubmed, Embase, CNKI, and Wanfang databases, and the odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the correlation. Finally,12 case-control studies comprising 1657 patients were included in our study. GSTP1 rs1695 gene polymorphism showed a significant correlation with granulocytopenia induced by platinum-based drugs (dominant genetic model: OR=1.60, 95% CI=1.19. 2.15, P=0.002; recessive genetic model: OR=3.72, 95% CI=1.73, 8.00, P=0.001; allelic genetic model: OR=1.76, 95% CI=1.34, 2.33, P=0.001). This gene polymorphism is not associated with thrombocytopenia (OR=0.87, 95% CI=0.47, 1.60, P=0.649). False-positive report probability showed that the association between polymorphism and adverse reactions is true. Sensitivity analysis showed that the results were stable. However, there was a certain publication bias in the included studies. In conclusion, the GSTP1 rs1695 gene polymorphism is associated with granulocytopenia induced by platinum-based drugs.

ß-elemene increases the sensitivity of gastric cancer cells to TRAIL by promoting the formation of DISC in lipid rafts.

ß-Elemene, an anti-cancer drug extracted from traditional Chinese medicinal herb, showed anti-tumor effects on gastric cancer cells. Our previous studies reported gastric cancer cells are insensitive to TRAIL. However, whether ß-elemene could enhance anti-cancer effects of TRAIL on gastric cancer cells is unknown. In our present study, ß-elemene prevented gastric cancer cell viability in dose-dependent manner, and when combined with TRAIL, obviously inhibited proliferation and promoted apoptosis in gastric cancer cells. Compared to ß-elemene or TRAIL alone, treatment with ß-elemene and TRAIL obviously promoted DR5 clustering as well as translocation of Caspase-8, DR5 and FADD into lipid rafts. This led to cleavage of Caspase-8 and the formation of death-inducing signaling complex (DISC) in lipid rafts. The cholesterol-sequestering agent nystatin partially reversed DR5 clustering and DISC formation, preventing apoptosis triggered by the combination of ß-elemene and TRAIL. Our results suggest that ß-elemene increases the sensitivity of gastric cancer cells to TRAIL partially by promoting the formation of DISC in lipid rafts.

Dietary exposure to methylmercury affects flight endurance in a migratory songbird.

Although there has been much speculation in the literature that methylmercury (MeHg) exposure can reduce songbird fitness, little is known about its effects on migration. Migrating songbirds typically make multiple flights, stopping to refuel for short periods between flights. How refueling at MeHg-contaminated stopover sites would contribute to MeHg bioaccumulation, and how such exposure could affect subsequent flight performance during migration has not been determined. In a dosing experiment we show that migratory yellow-rumped warblers (Setophaga coronata) rapidly accumulate dietary MeHg in blood, brain and muscle, liver and kidneys in just 1-2 weeks. We found that exposure to a 0.5 ppm diet did not affect vertical takeoff performance, but in 2-h wind tunnel flights, MeHg-treated warblers had a greater median number of strikes (landing or losing control) in the first 30 min, longer strike duration, and shorter flight duration. The number of strikes in the first 30 min of 0.5 ppm MeHg-exposed warblers was related to mercury concentration in blood in a sigmoid, dose-dependent fashion. Hyperphagic migratory songbirds may potentially bioaccumulate MeHg rapidly, which can lead to decreased migratory endurance flight performance.

DR5-Cbl-b/c-Cbl-TRAF2 complex inhibits TRAIL-induced apoptosis by promoting TRAF2-mediated polyubiquitination of caspase-8 in gastric cancer cells.

Ubiquitination of caspase-8 regulates TNF-related apoptosis-inducing ligand (TRAIL) sensitivity in cancer cells, and the preligand assembly complex plays a role in caspase-8 polyubiquitination. However, whether such a complex exists in gastric cancer cells and its role in TRAIL-triggered apoptosis is unclear. In this study, DR5, casitas B-lineage lymphoma-b (Cbl-b)/c-Cbl, and TRAF2 formed a complex in TRAIL-resistant gastric cancer cells, and Cbl-b and c-Cbl were the critical adaptors linking DR5 and TRAF2. Treatment with TRAIL induced caspase-8 translocation into the DR5-Cbl-b/c-Cbl-TRAF2 complex to interact with TRAF2, which then mediated the K48-linked polyubiquitination of caspase-8. The proteasome inhibitor bortezomib markedly enriched the p43/41 products of caspase-8 activated by TRAIL, indicating proteasomal degradation of caspase-8. Moreover, TRAF2 knockdown prevented the polyubiquitination of caspase-8 and thus increased TRAIL sensitivity. In addition, the inhibition of Cbl-b or c-Cbl expression and overexpression of miR-141 targeting Cbl-b and c-Cbl partially reversed TRAIL resistance by inhibiting the interaction between TRAF2 and caspase-8 and the subsequent polyubiquitination of caspase-8. These results indicate that the DR5-Cbl-b/c-Cbl-TRAF2 complex inhibited TRAIL-induced apoptosis by promoting TRAF2-mediated polyubiquitination of caspase-8 in gastric cancer cells.

CXCL12/SDF-1α induces migration via SRC-mediated CXCR4-EGFR cross-talk in gastric cancer cells.

Metastasis is the primary cause of mortality in patients with advanced gastric carcinoma, and multiple signaling pathways promote the development of this condition. Stromal cell-derived factor-1 (SDF-1α/CXCL12), the main ligand for CXC chemokine receptor-4 (CXCR4), serves an important role in gastric cancer cell migration. Previous studies have demonstrated that CXCL12 could also stimulate the secretion of epidermal growth factor receptor (EGFR) ligands, including amphiregulin and heparin-binding epidermal growth factor-like growth factor, from gastric cancer cells, resulting in an increase in the ability of migration. However, it remains to be elucidated whether CXCL12 activates EGFR intracellular signaling and therefore stimulates migration in gastric cancer. The present study demonstrated that three gastric cancer cell lines, SGC-7901, MGC-803 and BGC-823, all expressed CXCR4. The increased chemotactic migratory ability stimulated by CXCL12 was effectively abrogated by the CXCR4 antagonist, AMD3100. Furthermore, a rapid phosphorylation of Akt/extracellular signal-regulated kinase (ERK)/EGFR was demonstrated to be involved in CXCL12/CXCR4-induced gastric cancer cell migration. Knockdown of EGFR gene or the use of a monoclonal antibody against EGFR (C225) blocked the activation of ERK/Akt and partially prevented the ability of migration induced by CXCL12, which indicated that EGFR signaling is located downstream of CXCL12. In addition, it was also revealed that the activation of non-receptor tyrosine kinase c-steroid receptor co-activator (SRC) and the formation of the SRC/EGFR heterodimer are promoted by CXCL12, whereas the SRC inhibitor, PP2, blocks the SRC/EGFR heterodimer and the activation of EGFR, as well as CXCR4-meditated migration induced by CXCL12. The present results indicated that SRC mediates a potential CXCR4-EGFR cross-talk, and thereby utilizes the EGFR-Akt/ERK axis to promote cellular migration. The present study provided a novel insight into the underlying regulatory mechanisms of the CXCL12/CXCR4 pathway in gastric cancer cell migration.