Multidrug Resistance In Gastric Cancer Research Articles

The VEGFA-Induced MAPK-AKT/PTEN/TGFβ Signal Pathway Enhances Progression and MDR in Gastric Cancer.

Gastric cancer (GC) is a globally frequent cancer, in particular leading in mortality caused by digestive tract cancers in China. Vascular endothelial growth factor A (VEGFA) is excessively expressed in cancers including GC; its involvement in GC development, particularly in multidrug resistance (MDR), and the signal route it affects in GC remain unknown. To explore the roles VEGFA plays during progression and MDR formation in GC, we studied its function in a VEGFA-deleted GC cell platform. We initially assessed the importance of VEGFA in GC and MDR using database analysis. Then, using CCK8, wound healing, transwell, scanning electron microscopy, immunofluorescence, flow cytometry, and other techniques, the alterations in tumor malignancy-connected cell behaviors and microstructures were photographed and evaluated in a VEGFA-gene-deleted GC cell line (VEGFA-/-SGC7901). Finally, the mechanism of VEGFA in GC progression and MDR was examined by Western blot. Database analysis revealed a strong correlation between high VEGFA expression and a poor prognosis for GC. The results showed that VEGFA deletion reduced GC cell proliferation and motility and altered microstructures important for motility, such as the depolymerized cytoskeleton. VEGFA deletion inhibited the growth of pseudopodia/filopodia and suppressed the epithelial-mesenchymal transition (EMT). The occurrence of MDR is induced by overactivation of the MAPK-AKT and TGFβ signaling pathways, while PTEN inhibits these pathways. All findings suggested that VEGFA acts as a cancer enhancer and MDR inducer in GC via the MAPK-AKT/PTEN/TGFβ signal pathway.

SIVA-1 enhances acquired chemotherapeutic drug resistance of gastric cancer in vivo by regulating the ARF/MDM2/p53 pathway

SIVA-1 has been shown to affect apoptotic processes in various different cell lines, and SIVA-1 significantly contributes to the decreased responsiveness of cancer cells to some chemotherapy agents. However, whether SIVA-1 has potential application in gastric cancer remains unknown. Therefore, the objective of this investigation was to clarify the distinct function of SIVA-1 in chemotherapeutic drug resistance within a living murine model with gastric malignancy, and initially elucidate the underlying mechanisms. In an established multidrug-resistant gastric cancer xenograft mouse model, lentivirus, named Lv-SIVA-1, was injected into xenograft tumors, and increased the mRNA and protein expression of endogenous SIVA-1 in tumors. Immunohistochemical assays of xenograft tumor showed that SIVA-1 was significantly upregulated, and the protein expression levels of SIVA-1 were highly increased, as detected by Western blotting. In addition, we detected the role of SIVA-1 in cell proliferation and cell apoptosis in gastric cancer cells by TUNEL and found that SIVA-1 decreased tumor cell apoptosis and promoted tumor growth in vivo. Using a TMT assay between tumor tissues of experimental and control groups, differentially expressed proteins were examined and three potential biomarkers of multidrug resistance (ARF, MDM2, and p53) were screened. We further investigated the molecular mechanism by which SIVA-1 played an efficient role against chemotherapies and found that overexpressed SIVA-1 leads to increased ARF and MDM2 expression and suppressed expression of p53 in tumor tissue. In conclusion, SIVA-1 plays a significant role in the multidrug resistance of gastric tumors. In addition, overexpressed SIVA-1 positively regulates cell proliferation, adjusts cycle progression, and reduces the response to drug treatment for gastric cancer in an ARF/MDM2/p53-dependent manner. This novel research provides a basis for chemical management of gastric cancer through regulation of SIVA-1 expression.

Co-delivery of doxorubicin and paclitaxel via noisome nanocarriers attenuates cancerous phenotypes in gastric cancer cells

Gastric cancer (GC) is known as a deadly malignancy all over the world, yet none of the current therapeutic regimens have achieved efficacy. this current study has aimed to optimize and reduce treatment doses and overcome multidrug resistance in GC by developing optimum niosomal formulation for the delivery of doxorubicin (DXR), paclitaxel (PTX), and their co-delivery. The particles' size, polydispersity index (PDI), and entrapment efficacy (EE%) were optimized using statistical techniques, i.e., Box-Behnken and Central Composite Design. In contrast to soluble drug formulations, the release rate of medicines from nanoparticles were higher in physiological and acidic pH. Niosomes were more stable at 4 °C, compared to 25 °C. The MTT assay revealed that the IC50 of drug-loaded niosomes was the lowest among all developed formulations. The apoptosis-related genes (CASPASE-3, CASPASE-8, and CASPASE-9) and tumor suppressor genes (BAX, BCL2) were evaluated in cancer cells before and after treatment. In comparison to control cells and cells treated with soluble forms of DXR and PTX, while the expression of BCL2 decreased, the expression of BAX, CASPASE-3, CASPASE-8, and CASPASE-9 was enhanced in cells treated with drug-loaded niosomes. Drug-loaded niosomes inhibited colony formation capacity and increased apoptosis in human AGS gastric cancer cells. Our results indicate that co-delivery of DXR and PTX-loaded niosomes may be an effective and innovative therapeutic approach to gastric cancer.

Special AT-rich sequence binding protein 1 promotes multidrug resistance in gastric cancer by regulation of Ezrin to alter subcellular localization of ATP-binding cassette transporters.

Multidrug resistance is a primary factor in the poor response to chemotherapy and subsequent death in gastric cancer patients. However, the molecular mechanisms involved remain unclear. In this study, the high expression of special AT-rich sequence binding protein 1 (SATB1) in gastric cancer was found to be associated with reduced sensitivity to various chemotherapy drugs. Our results demonstrate that SATB1 can promote chemotherapy resistance in gastric cancer in vitro and in vivo. SATB1 exerts its effect by enhancing the activity of multiple ATP-binding cassette (ABC) transporters (P-glycoprotein, multidrug resistance-associated protein, and breast cancer resistance protein) in gastric cancer cell lines. We also found that SATB1 affects ABC transporters by altering the subcellular localization of the ABC transporter rather than its expression. Subsequently, we confirmed that Ezrin binds to various ABC transporters and affects their subcellular localization. In addition, we found that SATB1 can also bind to the Ezrin promoter and regulate its expression. In the present study, we elucidate the mechanism of SATB1-mediated multidrug resistance in gastric cancer, providing a basis for SATB1 as a potential target for reversal of resistance.

Impact of MiRNAs and LncRNAs on Multidrug Resistance of Gastric Cancer.

Multi-drug resistance (MDR) is characterized by the resistance of tumor cells to some antitumor drugs with different structures and mechanisms after the use of a single chemotherapy drug or even the first use of the drug. Notably, MDR has become the largest obstacle to the success of gastric cancer chemotherapies. Non-coding RNAs are defined as a class of RNAs that do not have the ability to code proteins. They are widely involved in important biological functions in life activities. Multiple lines of evidence demonstrated that ncRNAs are closely related to human cancers, including gastric cancer. However, the relationship between ncRNAs and MDR in gastric cancer has been reported, yet the mechanisms are not fully clarified. Therefore, in this review, we systematically summarized the detailed molecular mechanisms of lncRNAs (long noncoding RNAs) and miRNAs (microRNAs) associated with MDR in gastric cancer. Additionally, we speculate that the abnormal expression of ncRNAs is likely to be a novel potential therapeutic target reversing MDR for gastric cancer. Future therapeutics for gastric cancer will most likely be based on noncoding RNAs (ncRNAs) that regulate MDR-related genes.

APAF1-Binding Long Noncoding RNA Promotes Tumor Growth and Multidrug Resistance in Gastric Cancer by Blocking Apoptosome Assembly.

Chemotherapeutics remain the first choice for advanced gastric cancers (GCs). However, drug resistance and unavoidable severe toxicity lead to chemotherapy failure and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumor progression in many cancers, including GC. Here, through RNA screening, an apoptotic protease‐activating factor 1 (APAF1)‐binding lncRNA (ABL) that is significantly elevated in cancerous GC tissues and an independent prognostic factor for GC patients is identified. Moreover, ABL overexpression inhibits GC cell apoptosis and promotes GC cell survival and multidrug resistance in GC xenograft and organoid models. Mechanistically, ABL directly binds to the RNA‐binding protein IGF2BP1 via its KH1/2 domain, and then IGF2BP1 further recognizes the METTL3‐mediated m6A modification on ABL, which maintains ABL stability. In addition, ABL can bind to the WD1/WD2 domain of APAF1, which competitively prevent cytochrome c from interacting with APAF1, blocking apoptosome assembly and caspase‐9/3 activation; these events lead to resistance to cell death in GC cells. Intriguingly, targeting ABL using encapsulated liposomal siRNA can significantly enhance the sensitivity of GC cells to chemotherapy. Collectively, the results suggest that ABL can be a potential prognostic biomarker and therapeutic target in GC.

Tumor microenvironment responsive Mn3O4 nanoplatform for in vivo real-time monitoring of drug resistance and photothermal/chemodynamic synergistic therapy of gastric cancer

BackgroundPostoperative chemotherapy for gastric cancer often causes multidrug resistance (MDR), which has serious consequences for therapeutic effects. Individualized treatment based on accurate monitoring of MDR will greatly improve patient survival.ResultsIn this article, a self-enhanced Mn3O4 nanoplatform (MPG NPs) was established, which can react with glutathione to produce Mn2+ to enhance T1-weighted magnetic resonance imaging (MRI) and mediate in vivo real-time MDR monitoring. In vitro MRI results showed that MRI signals could be enhanced in the presence of hydrogen peroxide and glutathione and at acidic pH. In vivo MRI results indicated that MPG NPs could specifically target MDR cells, thereby realizing real-time monitoring of MDR in gastric cancer. Furthermore, MPG NPs have good chemodynamic activity, which can convert the endogenous hydrogen peroxide of tumor cells into highly toxic hydroxyl radical through Fenton-like reaction at acidic pH to play the role of chemodynamic therapy. In addition, Mn3O4 can significantly enhance the chemodynamic therapy effect because of its good photothermal conversion effect. Furthermore, in situ photothermal/chemodynamic synergistic therapy obtained remarkable results, the tumors of the mice in the synergistic therapy group gradually became smaller or even disappeared.ConclusionsMPG NPs have good biocompatibility, providing a good nanoplatform for real-time monitoring and precise diagnosis and treatment of MDR in gastric cancer.Graphical

Inhibition of apoptosis-regulatory protein Siva-1 reverses multidrug resistance in gastric cancer by targeting PCBP1.

Siva-1, as a pro-apoptotic protein, has been shown to induce extensive apoptosis in a number of different cell lines. In our previous study, we showed that overexpressed Siva-1 decreased the apoptosis of gastric cancer cells. So, we believe that it can also work as an anti-apoptotic protein. The present study aimed to determine the specific role of Siva-1 in anticancer drug resistance in gastric cancer in vivo and in vitro and preliminarily reveal the mechanism. A vincristine-resistant MKN-28/VCR gastric cancer cell line with stably downregulated Siva-1 was established. The effect of Siva-1 downregulation on chemotherapeutic drug resistance was assessed by measuring the IC50 and pump rate of doxorubicin. Proliferation, apoptosis of cells, and cell cycle were detected via colony formation assay and flow cytometry, respectively. Additionally, migration and invasion of cells was detected via wound healing and transwell assays. Moreover, we determined in vivo effects of LV-Siva-1-RNAi on tumor size, and apoptotic cells in tumor tissues were detected using TUNEL and hematoxylin and eosin staining. Siva-1 downregulation reduced the pump rate of doxorubicin and enhanced the response to drug treatment. Siva-1 negatively regulated proliferation and promoted apoptosis of cells by potentiality G2-M phase arresting. Inhibition of Siva-1 expression in MKN-28/VCR cells significantly weakened wound healing ability and decreased invasion ability. Poly(C)-binding protein 1 (PCBP1) was identified as a Siva-1-interacting protein in yeast two-hybrid screening. Semiquantitative RT-PCR and western blotting revealed that Siva-1 downregulation could inhibit expression of PCBP1, Akt, and NF-κB and eventually decrease the expression of MDR1 and MRP1. he current study demonstrated that the downregulation of Siva-1, which functions as a regulator of MDR1 and MRP1 gene expression in gastric cancer cells by inhibiting PCBP1/Akt/NF-κB signaling pathway expression, enhanced the sensitivity of gastric cancer cells to certain chemotherapies.

Silencing of ER-resident oxidoreductase PDIA3 inhibits malignant biological behaviors of multidrug-resistant gastric cancer.

Glycosylation is a common posttranslational modification of proteins, which plays a role in the malignant transformation, growth, progression, chemoresistance, and immune response of tumors. Disulfide isomerase family A3 (PDIA3) specifically acts on newly synthesized glycoproteins to promote the correct folding of sugar chains. Studies have shown that PDIA3 participates in multidrug-resistant gastric cancer (MDR-GC). In this study, we performed western blot analysis and immunohistochemistry to identify PDIA3 expression. Cell proliferation was assessed by CCK-8 assay. Transwell assays were used to detect the migration and invasion abilities of cells. Immunoprecipitation coupled to mass spectrometry (IP-MS) analysis was employed to identify PDIA3-interacting proteins and the associated pathways in MDR-GC cells. Glycoprotein interactions and translocation were detected by immunofluorescence assay. The results showed that PDIA3 knockdown significantly inhibited the proliferation, invasion, and migration abilities of MDR-GC cells. Kyoto Encyclopedia of Genes and Genomes analysis of the IP-MS results showed that PDIA3 was closely associated with focal adhesion pathways in MDR-GC cells. Additionally, important components of focal adhesion pathways, including fibronectin-1 (FN1) and integrin α5 (ITGA5), were identified as pivotal PDIA3-binding glycoproteins. Knockdown of PDIA3 altered the cellular locations of FN1 and ITGA5, leading to abnormal accumulation. In conclusion, our results suggest that knockdown of PDIA3 inhibited the malignant behaviors of MDR-GC cells and influenced the translocation of FN1 and ITGA5.

Babao Dan Reverses Multiple-Drug Resistance in Gastric Cancer Cells via Triggering Apoptosis and Autophagy and Inhibiting PI3K/AKT/mTOR Signaling

Multidrug resistance (MDR) is a critical reason for cancer chemotherapy failure. Babaodan (BBD) is a famous traditional Chinese patent medicine reported to have antigastric cancer activity. However, the roles and molecular mechanisms of the reversal of MDR of gastric cancer by BBD have not been well described until now. Therefore, the purpose of this study was to elucidate further the role of BBD in reversing the MDR of gastric cancer cells and its specific regulatory mechanism via in vitro experiments. To verify our results, MTT, Doxorubicin (DOX) staining, Rhodamin123 (Rho123) staining, DAPI staining, Annexin V-FITC, propidium iodide (PI), Cyto-ID, and western blot assays were performed. To determine whether BBD triggers apoptosis and autophagy through the PI3K/AKT/mTOR signaling, we also applied 3-methyladenine (3-MA), chloroquine (CQ), and 740Y-P (an activator of PI3K). The results showed that BBD reversed the MDR and induced apoptosis and autophagy of SGC7901/DDP cells. Pathway analyses suggested BBD inhibits PI3K/AKT/mTOR pathway activity and subsequent apoptosis-autophagy induction. Inhibition of autophagy with 3-MA and chloroquine (CQ) was performed to confirm that BBD promoted autophagy. PI3K agonist, 740Y-P, further verified BBD inhibition of PI3K/AKT/mTOR pathway activation. In conclusion, BBD may reverse the MDR of gastric cancer cells, induce apoptosis, and promote autophagy via inactivation of the PI3K/AKT/mTOR signaling pathway.

Siteng Fang Reverses Multidrug Resistance in Gastric Cancer: A Network Pharmacology and Molecular Docking Study.

Siteng Fang (STF) has been shown to inhibit migration, invasion, and adhesion as well as promote apoptosis in gastric cancer (GC) cells. However, whether it can reverse the multidrug resistance (MDR) of GC to chemotherapy drugs is unknown. Thus, we aimed to elucidate the mechanism of STF in reversing the MDR of GC. The chemical composition of STF and genes related to GC were obtained from the TCMNPAS(TCM Network Pharmacology Analysis System, TCMNPAS) Database, and the targets of the active ingredients were predicted using the Swiss Target Prediction Database. The obtained data were mapped to obtain the key active ingredients and core targets of STF in treating GC. The active component-target network and protein interaction network were constructed by Cytoscape and String database, and the key genes and core active ingredients were obtained. The biological functions and related signal pathways corresponding to the key targets were analyzed and then verified via molecular docking. A total of 14 core active ingredients of STF were screened, as well as 20 corresponding targets, which were mainly enriched in cancer pathway, proteoglycan synthesis, PI3K-AKT signaling pathway, and focal adhesion. Molecular docking showed that the core active ingredients related to MDR, namely quercetin and diosgenin, could bind well to the target. In summary, STF may reverse the MDR of GC and exert synergistic effect with chemotherapeutic drugs. It mediates MDR mainly through the action of quercetin and diosgenin on the PI3K/AKT signaling pathway. These findings are the first to demonstrate the molecular mechanism of STF in reversing MDR in GC, thus providing a direction for follow-up basic research.

Novel Pt(IV) complexes to overcome multidrug resistance in gastric cancer by targeting P-glycoprotein.

Systematic toxicity and drug resistance significantly limited FDA-approved platinum drugs for further clinical applications. In order to reverse the resistance (MDR) and enhance their anticancer efficiency, four Pt(IV) complexes (12-15) conjugating with P-glycoprotein (P-gp) inhibitors were designed and synthesized. Among them, complex 14 (IC50=3.37μM) efficiently reversed cisplatin resistance in SGC-7901/CDDP cell line and increased selectivity index (6.9) against normal HL-7702cell line. Detailed mechanisms in SGC-7901/CDDP cells assays revealed that complex 14 efficiently induced apoptosis via down-regulating expression of P-gp for enhanced intracellular uptake of platinum, arrested cells at G2/M phase, induced DNA damage and initiated mitochondrial apoptosis pathway. Further invivo studies demonstrated that the enhanced accumulation of complex 14 contributed to tumor inhibition of 75.6% in SGC-7901/CDDP xenografts, which was much higher than cisplatin (25.9%) and oxaliplatin (43%). Moreover, the low systematic toxicity made 14 a potential novel P-gp-mediated MDR modulator.

Hsa-miR-34a-5p reverses multidrug resistance in gastric cancer cells by targeting the 3′-UTR of SIRT1 and inhibiting its expression

Multidrug resistance (MDR) is a major obstacle to chemotherapy, which leads to ineffective chemotherapy, an important treatment strategy for gastric cancer (GC). The abnormality of microRNAs (miRNAs) is critical to the occurrence and progression of MDR in various tumors. In this study, hsa-miR-34a-5p was found to be decreased in multidrug resistant GC cells SGC-7901/5-Fluorouracil (SGC-7901/5-Fu) compared to the parental SGC-7901 cells. Overexpression of hsa-miR-34a-5p in SGC-7901/5-Fu cells promoted apoptosis and decreased migration and invasiveness after chemotherapy. In addition, overexpression of hsa-miR-34a-5p suppressed the growth of drug-resistant tumor in vivo. The mechanism of the effects of hsa-miR-34a-5p could include the regulation of the expression of Sirtuin 1 (SIRT1), P-glycoprotein (P-gp) or Multidrug resistance-related protein 1 (MRP1) through direct binding to the 3′-untranslated region (UTR) of SIRT1. Functional gain-and-loss experiments indicated that hsa-miR-34a-5p enhances the chemotherapy sensitivity of MDR GC cells by inhibiting SIRT1, P-gp and MRP1. In conclusion, hsa-miR-34a-5p can reverse the MDR of GC cells by inhibiting the expression of SIRT1, P-gp or MRP1.

The FENDRR/FOXC2 Axis Contributes to Multidrug Resistance in Gastric Cancer and Correlates With Poor Prognosis.

The dysregulation of long non-coding RNAs (lncRNAs) and transcription factors (TFs) is closely related to the development and progression of drug resistance in cancer chemotherapy. However, their regulatory interactions in the multidrug resistance (MDR) of gastric cancer (GC) has largely remained unknown. In this study, we report a novel oncogenic role of lncRNA FENDRR in conferring MDR in GC by coordinated regulation of FOXC2 expression at the transcriptional and posttranscriptional levels. In vitro and in vivo experiments demonstrated that downregulation of FENDRR expression remarkably decreased drug resistant ability of GC MDR cells while upregulation of FENDRR expression produced the opposite effect. FENDRR overexpression was observed in MDR GC cell lines, patient-derived xenografts, and clinical samples. And the high levels of FENDRR expression were correlated with poor prognosis in GC patients. Regarding the mechanism, FENDRR was revealed to increase proto-oncogene FOXC2 transcription by performing an enhancer-like role in the nucleus and by sponging miR-4700-3p in the cytoplasm. Both FOXC2 and miR-4700-3p were shown to be functionally involved in the FENDRR-induced chemoresistance. In addition, there is a positive correlation between FENDRR and FOXC2 expression in clinic and the overexpressed FOXC2 indicated a poor prognosis in GC patients. Collectively, our findings provide a new perspective for the lncRNA-TF regulatory interaction involved in MDR, suggesting that targeting the FENDRR/FOXC2 axis may be an effective approach to circumvent GC chemoresistance.

Multidrug Resistance of Gastric Cancer: The Mechanisms and Chinese Medicine Reversal Agents.

Chemotherapy is the main clinical treatment method of gastric cancer. Multidrug resistance (MDR) has become a common phenomenon with the development of tumors, which alleviates the effect of chemotherapy and makes it difficult to break the bottleneck of survival rate of advanced gastric cancer. Therefore, the exploration of MDR reversal agents for gastric cancer is the focus and also the difficulty of current treatment. Currently, the researches on the mechanisms of drug resistance in gastric cancer have been continuously deepened, which reveal different pathways and targets of MDR, laying a solid foundation for studying reversal agents. As a kind of natural medicine, traditional Chinese medicine (TCM) owns the characteristics of low toxicity, high safety and effectiveness. It can inhibit the occurrence, growth and metastasis of tumors, and reverse MDR via multiple pathways and mechanisms, the pathological function of which has become a research hotspot in recent years. TCM reversers are mainly divided into Chinese medicine monomers, Chinese patent medicines, and Chinese herbal compounds. With certain quantity and advantage, TCM reversers for MDR play an important role in the clinical treatment and show great potential in gastric cancer.

Silencing of the ARK5 gene reverses the drug resistance of multidrug-resistant SGC7901/DDP gastric cancer cells.

For several years, the multidrug resistance (MDR) of gastric cancer cells has been a thorny issue worldwide regarding the chemotherapy process and needs to be solved. Here, we report that the ARK5 gene could promote the multidrug resistance of gastric cancer cells in vitro and in vivo. In this study, LV-ARK5-RNAi lentivirus was used to transfect the parental cell line SGC7901 and MDR cell line SGC7901/DDP to construct a stable model of ARK5 interference. Subsequently, the cells were treated with four chemotherapeutic drugs, cisplatin (DDP), adriamycin (ADR), 5-fluorouracil (5-FU) and docetaxel (DR) and were subjected to the CCK8, colony formation, adriamycin accumulation and retention, cell apoptosis and other assays. The study found that, in vitro, the expression of ARK5 in MDR gastric cancer cells was significantly higher than that in parental cells. Additionally, when treated with different chemotherapeutic drugs, compared with parental cells, MDR cells also had a higher cell survival rate, higher colony formation number, higher drug pump rate, and lower cell apoptosis rate. Additionally, in xenograft mouse models, MDR cells with high ARK5 expression showed higher resistance to chemotherapeutic drugs than parental cells. Overall, this study revealed that silencing the ARK5 gene can effectively reverse the drug resistance of MDR gastric cancer cells to chemotherapeutic drugs, providing insights into the mechanism of this process related to its inhibition of the active pump-out ability of MDR cells.

Siva‑1 regulates multidrug resistance of gastric cancer by targeting MDR1 and MRP1 via the NF‑κB pathway.

Siva-1 is a well-known anti-apoptosis protein that serves a role in multiple types of cancer cells. However, whether Siva-1 affects multidrug resistance via the NF-κB pathway in gastric cancer is currently unknown. The present study aimed to determine the possible involvement of Siva-1 in gastric cancer anticancer drug resistance in vitro. A vincristine (VCR)-resistant KATO III/VCR gastric cancer cell line with stable Siva-1 overexpression was established. The protein expression levels of Siva-1, NF-κB, multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1) were detected via western blotting. The effect of Siva-1 overexpression on anticancer drug resistance was assessed by measuring the 50% inhibitory concentration of KATO III/VCR cells to VCR, 5-fluorouracil and doxorubicin. The rate of doxorubicin efflux and apoptosis were detected by flow cytometry. Additionally, colony formation, wound healing and Transwell assays were used to detect the proliferation, migration and invasion of cells, respectively. The results of the current study revealed that the Siva-1-overexpressed KATO III/VCR gastric cancer cells exhibited a significantly decreased sensitivity to VCR, 5-fluorouracil and doxorubicin. The results of flow cytometry revealed that the percentage of apoptotic cells decreased following overexpression of Siva-1. The colony formation assay demonstrated that cell growth and proliferation were significantly promoted by Siva-1 overexpression. Additionally, Siva-1 overexpression increased the migration and invasion of KATO III/VCR cells in vitro. Western blot analysis determined that Siva-1 overexpression increased NF-κB, MDR1 and MRP1 levels. The current study demonstrated that overexpression of Siva-1, which functions as a regulator of MDR1 and MRP1 gene expression in gastric cancer cells via promotion of NF-κB expression, inhibited the sensitivity of gastric cancer cells to certain chemotherapies. These data provided novel insight into the molecular mechanisms of gastric cancer, and may be of significance for the clinical diagnosis and therapy of patients with gastric cancer.

Research on Gastric Cancer’s Drug-resistant Gene Regulatory Network Model

Objective: Based on bioinformatics, differentially expressed gene data of drug-resistance in gastric cancer were analyzed, screened and mined through modeling and network modeling to find valuable data associated with multi-drug resistance of gastric cancer. Methods: First, data sets were preprocessed from three aspects: data processing, data annotation and classification, and functional clustering. Secondly, based on the preprocessed data, each classified primary gene regulatory network was constructed by mining interactions among the genes. This paper computed the values of each node in each classified primary gene regulatory network and ranked these nodes according to their scores. On the basis of this, the appropriate core node was selected and the corresponding core network was developed. Results and Conclusion:: Finally, core network modules were analyzed, which were mined. After the correlation analysis, the result showed that the constructed network module had 20 core genes. This module contained valuable data associated with multi-drug resistance in gastric cancer.

MiRNA-765 mediates multidrug resistance via targeting BATF2 in gastric cancer cells.

Elucidation of the mechanisms underlying multidrug resistance (MDR) is required to ensure the efficacy of chemotherapy against gastric cancer (GC). To investigate this issue, here we identified that microRNA‐765 (miRNA‐765) is up‐regulated both in MDR GC cell lines and in specimens from patients who are not responding to chemotherapy. In addition, down‐regulation of miRNA‐765 increased the sensitivity of GC cells to anticancer drugs, whereas its overexpression had the opposite effect. Moreover, miRNA‐765 suppressed drug‐induced apoptosis and positively regulated the expression of MDR‐related genes. Finally, we showed that the basic leucine zipper ATF‐like transcription factor 2, a tumor suppressor gene, is the functional target of miRNA‐765. In summary, these results suggest that miRNA‐765 may promote MDR via basic leucine zipper ATF‐like transcription factor 2 in GC cells.

The Roles of microRNAs in Multidrug-Resistance Mechanisms in Gastric Cancer.

Multidrug resistance (MDR) is one of the most significant reasons for the chemotherapeutics failure in gastric cancer. Although accumulating investigations and researches have been made to elucidate the mechanisms of multidrug resistance, the detail is far from completely understood. The importance of microRNAs in cancer chemotherapeutic resistance has been demonstrated recently, which provides a new strategy to overcome multidrug resistance. The different mechanisms are related to the phenomena of MDR itself and the roles of miRNAs in these multi-mechanisms by which MDR is acquired. In turn, the aim of this review was to summarize recent publications of microRNAs in regulating MDR in gastric cancer, thereby potentially developing as targeted therapies. Further unraveling the roles of microRNAs in MDR mechanisms including the ATP-binding cassette (ABC) transporter family, autophagy induction, cancer stem cell regulation, hypoxia induction, DNA damage and repair, epigenetic regulation, and exosomes in gastric cancer will be helpful for us to win the battle against it.