Gastric Cancer Cells

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Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α- ATF4-xCT pathway

Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α- ATF4-xCT pathway

In this study, we demonstrated that mitochondrial dysfunction induced by oligomycin and antimycin A might enhance cisplatin resistance in human gastric cancer cells through increased xCT expression and intracellular GSH levels, as well as through the ROS activation of the GCN2-eIF2α-ATF4 pathway. Moreover, high xCT expression and the activation of the GCN2-eIF2α-ATF4 pathway were observed in cisplatin-resistant gastric cancer cells. In addition, high xCT expression in gastric cancer was associated with the poor prognosis of patients under adjuvant chemotherapy treatment. These results provided evidence for the first time to suggest that the ROS-activated GCN2-eIF2α-ATF4-xCT pathway is retrograde signaling that contributes to mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells (Figure 9D). In our previous studies, we found that mitochondrial DNA mutations and defects in mitochondrial enzymes in gastric cancers might contribute to cancer progression and chemoresistance [5, 6]. In this study, we further demonstrated that xCT might be an important link between mitochondrial dysfunction and cisplatin resistance.
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UFM1 suppresses invasive activities of gastric cancer cells by attenuating the expression of PDK1 through PI3K/AKT signaling

UFM1 suppresses invasive activities of gastric cancer cells by attenuating the expression of PDK1 through PI3K/AKT signaling

The PDK1 molecule contains 36 lysines, 27 of which are located in the N-terminal kinase domain and 9 of which are located in the C-terminal platelet-leukocyte C kinase substrate homolog domain (C-terminal pleckstrin homology domain) [28, 29]. PDK1 belongs to the AGC protein kinase family (cAMP and cGMP-dependent pro- tein kinase C), which phosphorylates many downstream proteins such as AKT, p90RSK, p70S6K, SGK and PKC [28, 30–32]. Studies have shown that blocking the inter- action between PDK1 and AKT can inhibit the growth and metastasis of melanoma [33]. Therefore, we used siRNA to knockdown PDK1 in AGS cells with stable downregulated expression of UFM1. In our study, we thought that using the same cell line for overexpression and knockdownof the target gene for cell function assay could avoid the interference of cell line changes on the experimental results, and it can also reflect the effect of genetic changes on the function of the cell line. We found that also in many literatures also overexpressed and knocked out using the same cell line [34, 35]. We tested the expression level of UFM1 protein in different gastric cancer cell lines and found that AGS was at a medium level. Therefore, we mainly chose AGS for over- expression and knockdownthen for cell function experi- ments. In addition, we verified these results in HGC-27 gastric cancer cells. Although the expression level of CDK5RAP3 in HGC-27 was low, but the experiment after knocking down and overexpression the target gene also re- flects the effect of the gene on cell function. Furthermore, we found that the inhibitory effect of UFM1 on gastric can- cer cell EMT was also prevented when PDK1 was knocked down. Studies by Paolo Armando et al. have shown that PDK1 deletion can affect the EMT process in endothelial Table 2 Univariate analysis of the correlation between
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<p>Effect of overexpression of Oct4 and Sox2 genes on the biological and oncological characteristics of gastric cancer cells</p>

<p>Effect of overexpression of Oct4 and Sox2 genes on the biological and oncological characteristics of gastric cancer cells</p>

In this study, we overexpreessed Oct4 and Sox2 (using a lentiviral vector) in gastric cancer cells. Using the scratch-wound migration assay and transwell migration and invasion assays, it was found that the invasion ability of gastric cancer cells overexpressing Oct4 and Sox2 was increased. Using an MTS assay, it was found that the proliferation ability of the cells was also signi fi cantly increased. In the tumor formation experiment in nude mice, the tumor formation of gastric cancer cells over- expressing Oct4 and Sox2 was signi fi cantly faster and the tumors were consequently larger and heavier. The results strongly show that Sox2 and Oct4 play important roles in the proliferation, invasion, and metastasis of gas- tric cancer cells. In addition, fl uorescence quantitative PCR and Western blotting showed that the cytokine levels of gastric cancer cells overexpressing Oct4 and Sox2 were signi fi cantly increased. These results suggest that Sox2 and Oct4 increase stem cell characteristics and promote the regeneration and differentiation of tissue cells. It is speculated that Sox2 and Oct4 have a synergistic effect regarding promoting the biological, oncological, and stem cell characteristics of gastric cancer.
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Original Article Knockdown of miR-24 suppresses the proliferation, migration and invasion of gastric cancer cells and predicts a poor prognosis in gastric cancer

Original Article Knockdown of miR-24 suppresses the proliferation, migration and invasion of gastric cancer cells and predicts a poor prognosis in gastric cancer

Abstract: Objective: Gastric cancer (GC) is one of the leading causes of cancer death worldwide. MicroRNAs have recently emerged as key regulators of GC. In this study, we tried to investigate the effects of knockdown of miR- 24 on the proliferation, migration and invasion of gastric cancer cells. Methods: A total of 28 GC tissue samples and matched non-tumor tissue samples were obtained from surgery patients at First Affiliated Hospital of Nanjing Medical University between 2013-2014. Human GC cell lines MGC803, AGS, BGC823 and SGC7901 were cultured. MiRNA mimics and their appropriate negative control were used to knock down the target gene. QRT-PCR, Western blot were used to test the expression of the gene and MTT assay, cell migration and invasion assay were adopted to evaluate the cells’ proliferation, migration and invasion. Results: Results showed that miR-24 was up-regulated in GC tissues and cell lines. Knockdown of miR-24 remarkably suppressed cell proliferation of GC cell lines SGC7901. Moreover, knocking down on miR-24 also significantly suppressed migration and invasion of GC cells SGC7901. What’s more, the results of viewing on patients showed the patients in the miR-24-positive group had a poorer prog- nosis than did the patients in miR-24-negative group. Conclusion: Taken together, miR-24 could suppress GC cells growth and motility. MiR-24 acts as a predictor of a poor prognosis in patients with GC.
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NLRP6, decreased in gastric cancer, suppresses tumorigenicity of gastric cancer cells

NLRP6, decreased in gastric cancer, suppresses tumorigenicity of gastric cancer cells

To further verify whether FOXO3 regulated the NLRP6 gene expression, gastric cancer cells were trans- fected with FOXO3 siRNA. FOXO3 knockdown led to a significant downregulation in the protein expression (Figure 5E), mRNA expression (Figure 5F), and pro- moter activity (Figure 5G) of NLRP6. Furthermore, a PI3K inhibitor LY294002 was applied to gastric cancer cells exposed to H. pylori. As illustrated in Figure 5H, LY294002 treatment in gastric cancer cells remarkably sup- pressed the effects of H. pylori infection on the phos- phorylation of FOXO3 and the protein levels of NLRP6. Furthermore, H. pylori led to a significant downregulation of the amount of mRNA (Figure 5I) and the promoter activity (Figure 5J) of NLRP6 gene, while LY294002 treatment displayed reversed effects. LY294002 treatment can rescue the effects of H. pylori infection. These data suggested that downregulation of NLRP6 expression in gastric cancers may be associated with H. pylori/AKT/ FOXO3 signaling.
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<p>Knockdown of ROS proto-oncogene 1 inhibits migration and invasion in gastric cancer cells by targeting the PI3K/Akt signaling pathway</p>

<p>Knockdown of ROS proto-oncogene 1 inhibits migration and invasion in gastric cancer cells by targeting the PI3K/Akt signaling pathway</p>

colorectal cancer. 19 However, no study has clari fi ed the role of ROS1 in gastric cancer. In the present study, TCGA database was applied to analyze the mRNA expression of ROS1 in gastric cancer. The results showed that ROS1 was overexpressed in gastric cancer compared to normal mucosa samples. Higher level of ROS1 was related to depth of invasion, lymph node metastasis, dis- tant metastasis and TNM staging. In addition, higher expression predicted worse prognosis of patients with gastric cancer. Then, we knocked down ROS1 expression in gastric cancer BGC-823 and SGC-7901 cells. Davies KD et al have demonstrated that ROS1 inhibition mediated by crizotinib and NVP-TAE684 (both are ALK inhibitors with activities against ROS1) inhibits HCC78 cell proliferation. 20 We found that ROS1 knock- down mediated by speci fi c shRNA transfection signi fi - cantly reduced cell viability and inhibited colony formation of gastric cancer cells (BGC-823 and SGC- 7901). Deng G et al have observed similar results in intrahepatic cholangiocarcinoma cells, 18 which are con- sistent with our studies. Cell cycle is a highly ordered process that tightly regulated by multiple cell cycle- related regulators. 21 Cell cycle dysregulation is the hall- mark of cancer. 22 Cell cycle arrest can lead to inhibition of cell growth. 23 Therefore, in our study, we further con fi rmed whether cell growth inhibition in gastric can- cer cells was associated with cell cycle arrest. Flow cytometric analysis showed that ROS1 knockdown arrested the cell cycle at G1 phase. The observations indicate that ROS1 knockdown may inhibit proliferation and clonogenic growth of gastric cancer cells in vitro by inducing cell cycle arrest.
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Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells

Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells

In order to verify the potential anti-cancer properties of itraconazole, we firstly tested whether it could inhibit the proliferation of gastric cancer cells. To this end, MKN45 and AGS cells were treated with increasing con- centrations of itraconazole and cell proliferation was determined with CCK-8 assay. As shown in Fig. 1a, itraconazole could inhibit cell proliferation in a dose- dependent manner in both cell lines. Furthermore, colony formation assay showed that itraconazole could dramatically inhibit the colony formation in a concentra- tion dependent manner, reflected by fewer and smaller colonies in the drug-treated group (Fig. 1b). More inter- estingly, when cells were treated with 5-FU and itracona- zole concomitantly, itraconazole could greatly increase the cytotoxicity of 5-FU to gastric cancer cells (Fig. 1c). The antitumor properties of itraconazole in gastric can- cer were further evaluated using tumor xenograft model. As shown in Fig. 1d, Itraconazole inhibited growth of AGS and MKN45 cells xenografts as a single agent and in combination with 5-FU therapy. Taken together, these data suggested that itraconazole acts as a proliferation suppressor in gastric cancer cells.
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Circ-104916 is downregulated in gastric cancer and suppresses migration and invasion of gastric cancer cells

Circ-104916 is downregulated in gastric cancer and suppresses migration and invasion of gastric cancer cells

In our previous study, the microarray results suggested that the expression of circRNAs in gastric carcinoma tissues was abnormal compared with adjacent normal tissues (Figure S1). The expression of circ-104916 was reduced in GC tissues. To confirm hsa-circ-104916 expression in GC, qRT-PCR was performed in 70 pairs of human GC specimens and their adja- cent noncancerous tissue samples. More than 50% reduction in circ-104916 expression was observed in 65.7% (46/70) of GC tissues (Figure 1A). The expression of circ-104916 was significantly lower in GC tissues than in the corresponding adjacent noncancerous tissues (Figure 1B). Theses results suggested that circ-104916 was downregulated in GC tissues, which was consistent with our microarray result.
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Original Article Decreased expression of let-7f associates with the poor prognosis of glioma patients

Original Article Decreased expression of let-7f associates with the poor prognosis of glioma patients

The let-7 family is a high conserved family of miRNAs, including fourteen members [24]. Currently, many members of let-7 family were reported to be associated with cancer tumo- rigenesis and progression. Let-7a had been reported to inhibit growth and migration of breast cancer cells [25]. Han et al. demonstrat- ed that let-7b could suppress invasion and migration of gastric cancer cells through direct- ly targeting the tumor metastasis-associated gene ING1 [26]. And let-7f was also proved to play regulatory roles in several types of cancer, such as gastric cancer, breast cancer, hepato- cellular carcinoma and so on [15-17]. Then weather let-7f participates in the development of glioma or affects the clinical outcome re- quires further investigation.
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Silencing NKD2 by promoter region hypermethylation promotes gastric cancer invasion and metastasis by up-regulating SOX18 in human gastric cancer

Silencing NKD2 by promoter region hypermethylation promotes gastric cancer invasion and metastasis by up-regulating SOX18 in human gastric cancer

In this study, we detected the methylation status of NKD1 and NKD2 in human gastric cancer cell lines and primary cancer tissue samples. The expression levels of NKD1 and NKD2 were regulated by promoter region methylation. NKD1 was infrequently methylated in primary gastric cancer, while NKD2 was frequently methylated. Methylation of NKD2 was related to cell differentiation, TNM stage, distant metastasis and overall survival, but no association was found between NKD1 methylation and any of the analyzed clinical factors. Therefore, we mainly focused our study on NKD2 in gastric cancer. NKD2 inhibited cell proliferation, colony formation, and induced G2/M phase arrest. Re-expression of NKD2 sensitized gastric cancer cells to docetaxel. These results suggest that NKD2 methylation is involved in gastric cancer prognosis and metastasis. It may serve
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Circ_0027599/PHDLA1 suppresses gastric cancer progression by sponging miR-101-3p.1

Circ_0027599/PHDLA1 suppresses gastric cancer progression by sponging miR-101-3p.1

To verify circ_0027599 expression in samples of the gastric cancer, 78 cases were collected for measuring circ_0027599 expression by real time RT-PCR. The data showed that the average level of circ_0027599 was lower in 78 pairs of cancer tissues than it in adja- cent normal tissues (Fig.  5a). In gastric cancer cells, circ_0027599 was also lower in the blood samples of gastric cancer than it in the healthy persons (Fig. 5b). To learn the relationship of circ_0027599 levels with clinic features of gastric cancer. The analyzed results showed that circ_0027599 was not related the ages of gastric cancer patients (Table  1). There was a nega- tive relationship between circ_0027599 expression with tumor size, depth of invasion, lymph node dis- tant metastasis, distant metastasis and TNM staging (Table 1). We also analyzed the relationship between circ_0027599 and PHLDA1 levels in gastric cancer tissues, and the data indicated that circ_0027599 expression was positively associated with PHLDA1 expression (Fig.  5c). MiR-101 was up-regulated in
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MK-2206 co-treatment with 5-fluorouracil or doxorubicin enhances chemosensitivity and apoptosis in gastric cancer by attenuation of Akt phosphorylation

MK-2206 co-treatment with 5-fluorouracil or doxorubicin enhances chemosensitivity and apoptosis in gastric cancer by attenuation of Akt phosphorylation

We first examined the antiproliferative effect of MK-2206 as a single agent in gastric cancer cells SGC-7901 and MKN45 (Figure 1A). MK-2206 inhibited the proliferation of gastric cancer cells in a dose- and time-dependent manner (P,0.05; two-way ANOVA followed by Bonferroni post-hoc tests), reaching a plateau at 2–8 μ M in SGC-7901 cells (P = 0.337, 0.787, and 0.728 for 24, 48, and 72 hours’ treatment, respec- tively; one-way ANOVA) or at 2–4 μ M in MKN45 cells (P = 0.990, 0.817, and 0.295 for 24, 48, and 72 hours’ treatment, respectively; 2 vs 4 μ M, Tukey’s test). MK-2206 showed the IC 50 values of 22.92 ± 4.00, 13.68 ± 2.04, and 8.55 ± 1.88 μ M (estimated mean ± 95% confidence interval) in SGC-7901 cells and 19.21 ± 1.45, 13.10 ± 0.96, and 9.11 ± 1.43 μ M (estimated mean ± 95% confidence interval) in MKN45 cells 24, 48, and 72 hours posttreatment, respectively (Table 1). Colony for- mation assay confirmed that 1 μ M of MK-2206 resulted in a significant inhibitory effect in SGC-7901 cells (18.13% ± 1.8% vs 38.87% ± 5.9%; P = 0.004, Student’s t-test; Figure 1B).
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RPS15a Silencing Suppresses Cell Proliferation and Migration of Gastric Cancer

RPS15a Silencing Suppresses Cell Proliferation and Migration of Gastric Cancer

Purpose: Information on the possible role of the ribosomal protein S15a (RPS15a) in gastric cancer is scarce. The aim of this study was to evaluate the impact of RPS15a gene expression on the growth and cell cycle of gastric cancer cells in vitro and in vivo. Materials and Methods: RPS15a mRNA expression was examined in cancer tissues and their corresponding adjacent normal tis- sues of 40 gastric adenocarcinoma patients. Next, RPS15a was knocked down using a lentivirus-mediated RNA interference (short hairpin RNA) system in the gastric cancer cell line BGC823. The effect of RPS15a knockdown was examined using CCK-8 assay, cell scratch test, colony formation assay, and flow cytometry. Finally, in nude mice, a tumorigenicity test was performed, and the tumor volume and weight were measured.
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<p>PTPRU, As A Tumor Suppressor, Inhibits Cancer Stemness By Attenuating Hippo/YAP Signaling Pathway</p>

<p>PTPRU, As A Tumor Suppressor, Inhibits Cancer Stemness By Attenuating Hippo/YAP Signaling Pathway</p>

PTPRU belongs to the protein tyrosine phosphatase (PTP) family 11–13 that regulates a variety of important cellular processes. 14,15 The role of PTPRU in tumor progression is contradictory. 17 PTPRU has been reported to inhibit cell pro- liferation by decreasing β -catenin tyrosine phosphorylation. 18 In contrast, another study showed that endogenous PTPRU is required for glioma growth. 19 It is also reported that knock- down of PTPRU inhibits cell growth and motility of gastric cancer cells. 20 These fi ndings suggested that the role of PTPRU during cancer development depends on the cellular signaling context and cell type. However, the role of PTPRU in cancer stemness has remained elusive.
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Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer

Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer

Drug ‘repurposing’ is the identification of new therapeutic applications for drugs that have received US FDA approval for another purpose. Due to the reduced length and cost of research and trial phases, drug repurposing is more affordable and achievable than novel drug discovery [24]. Auranofin is a drug that is approved for the treatment of rheumatoid arthritis. Recently, treatment with AF was discovered to inhibit TrxR and induce ROS in cancer cells, which was associated with high in vitro and in vivo potency of AF against cancer cells [11, 25]. With the goal of potential repurposing AF for the treatment of gastric cancer, our preclinical studies presented here demonstrate that AF could induce ROS in the gastric cancer cells. Here, we also showed for the first time that treatment with AF was linked to and could induce lethal oxidative, ER stress-based UPR responses and mitochondrial dysfunction in gastric cancer cells. Furthermore, Co-treatment with NAC fully reversed the AF-induced increase in ROS and cell death, served to reinforce the role of ROS as an effector.
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CHD5 is down-regulated through promoter hypermethylation in gastric cancer

CHD5 is down-regulated through promoter hypermethylation in gastric cancer

that functions to stabilize p53, the tumor suppressor inac- tivated in more than half of human cancers [15]. CHD5 is present at a gene locus (1p36.31) deleted in about 35% of neuroblastoma [16]. CHD5 was previously thought to be specifically expressed in the nervous system, but its role in cancer in other tissues is starting to emerge [17]. CHD5 gene was found significantly deleted in glioma [18]. Apart from gene deletion, CHD5 can be suppressed by other mechanisms. In some cases of neuroblastoma, there are evidence that CHD5 expression is epigenetically sup- pressed by promoter hypermethylation [19], although this observation was not confirmed by another study [20]. Recently, the CHD5 promoter has been found to be meth- ylated in small subsets of breast (4.4%), colon (10%), ovarian (15%) and glioma (17%) tumors [17,20], sug- gesting epigenetic silencing of CHD5 by methylation may play a partial role in tumorigenesis in these tissues. Here we found that, in contrast to other types of cancer reported so far, CHD5 was frequently hypermethylated in gastric cancer (73% of tumors and 100% cell lines). The ectopic expression of CHD5 in gastric cancer cells led to a significant growth inhibition. This striking correlation of
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CD44 but not CD24 expression is related to poor prognosis in non-cardia adenocarcinoma of the stomach

CD44 but not CD24 expression is related to poor prognosis in non-cardia adenocarcinoma of the stomach

and lymphatic invasion. However, although the present study found a trend towards shorter survival in CD24(−) compared with CD24(+) patients, the difference was not significant. Duckworth et al. detected CD24 expression in gastric parietal cells and showed that it regulated apoptosis and the response to Helicobacter felis infection in a mouse model [25]. However, the current study found no significant association between Helicobacter infection and CD24 expression. One possible explan- ation for the significant association between CD44 and survival may be related to the stem cell function of CD44(+) cells [26-29]. In 2009, Takaishi et al. first dem- onstrated the existence of CD44(+) cells endowed with stem cell properties in gastric tumors. They reported that CD44(+) gastric cancer cells showed the stem cell characteristics of self-renewal and the ability to form dif- ferentiated progeny and give rise to CD44(−) cells. Takaishi et al. further verified CD44 as a cell surface marker of gastric CSCs in several human gastric cancer cell lines, and demonstrated that CD44(+) gastric cancer cells showed increased resistance to chemotherapy- or radiation-induced cell death [29]. Liu et al. reported that CD44 was a direct and relevant downstream target of miR-34a in prostate cancer. CD44 protein levels were decreased in cells over-expressing miR-34a, and knock down of CD44 functionally mimicked the miR-34a ef- fects of inhibition of tumor development and metastasis [30]. We therefore considered that higher expression of CD44 in gastric cancer cells may represent a higher per- centage of CSCs, thus explaining why CD44(+) patients demonstrate poorer overall survival than CD44(−) pa- tients. Further studies are warranted to investigate the mechanisms of miRNA regulation of CSCs.
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Intelectin 1 suppresses tumor progression and is associated with improved survival in gastric cancer

Intelectin 1 suppresses tumor progression and is associated with improved survival in gastric cancer

in altered transcript levels of 1592 human genes, including 547 up-regulated and 1045 down-regulated ones, and regulation of cellular process was the top-ranked function of ITLN1 in gastric cancer cells (Figure S1). Notably, among 331 ITLN1-altered (91 up-regulated and 240 down-regulated) genes involved in the cellular process (Table S1), HNF4α was identified as the most up-regulated one (Figure 1B). Real-time quantitative RT-PCR and western blot further demonstrated that stable transfection of ITLN1 increased the transcript and protein levels of HNF4α, when compared to those stably transfected with empty vector (mock) (Figure 1C and Figure 1D). In addition, administration of recombinant ITLN1 protein (1 and 2 μg/ml) into cultured gastric cancer cell lines also markedly induced the HNF4α expression at 24 and 36 hrs post-administration (Figure 1E). Moreover, the nuclear translocation of β-catenin, a target gene of HNF4α [20] (Figure S2A and Figure S2B), was correspondingly decreased in SGC-7901 and AGS cells stably transfected with ITLN1 than mock cells (Figure 1C, Figure 1D, and Figure S2C). To further examine the effects of ITLN1 on HNF4α expression, we performed the ITLN1 knockdown experiments. Stable transfection of short hairpin RNA (shRNA) specific for ITLN1 (sh-ITLN1) led to reduced ITLN1 secretion (Figure 1F, Figure 1G, and Figure S3A), decreased HNF4α expression (Figure 1F, Figure 1G, and Figure S3B), and increased nuclear translocation of β-catenin (Figure 1F and Figure S2D). Moreover, stable over-expression or knockdown of ITLN1 in gastric cancer cells decreased and increased the β-catenin activity and transcription of downstream genes axin 2 (AXIN2) [21], cyclin D2 (CCND2) [22], runt-related transcription factor 2 (RUNX2) [23], and matrix metallopeptidase 3 (MMP3) [24], respectively, which was abolished by knockdown or ectopic expression of HNF4α (Figure 1H, Figure S2E, Figure S2F, and Figure S3B). Overall, these results demonstrated that ITLN1 considerably facilitated the HNF4α expression at transcriptional levels in gastric cancer cells.
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Tetrahydroxystilbene Glucoside Exerts Cytoprotective Effect against Hydrogen Peroxide-induced Cell Death Involving ROS Production and Antioxidant Enzyme Activation

Tetrahydroxystilbene Glucoside Exerts Cytoprotective Effect against Hydrogen Peroxide-induced Cell Death Involving ROS Production and Antioxidant Enzyme Activation

Epithelial injury caused by reactive oxygen species including hydrogen peroxide plays a critical role in the pathogenesis of gastric disorders. Tetrahydroxystilbene glucoside is an active component extracted from Polygonum multiflorum, a famous traditional Chinese herb. This study aimed to evaluate the protective effect of tetrahydroxystilbene glucoside on hydrogen peroxide-induced oxidative stress on non-malignant gastric epithelial cells and to see if these protective actions can be extended to gastric cancer cells. The results from MTT assay showed that incubating gastric epithelial cells and gastric cancer cells with 200 μΜ hydrogen peroxide for 24 h significantly decreased cell viability, whereas pre-incubating cells with 10 μΜ tetrahydroxystilbene glucoside for 24 h protected the cells against hydrogen peroxide cell damage, and more significantly in gastric epithelial cells. Using 2′,7′-dichlorofluorescin diacetate, we found that tetrahydroxystilbene glucoside inhibited the production of intracellular reactive oxygen species in gastric epithelial cells and gastric cancer cells. In addition, it induced the expression of antioxidant enzymes hemeoxygenase-1 and NADPH quinone oxidoreductase-1. These results demonstrated that tetrahydroxystilbene glucoside exerted stronger cytoprotective effect against peroxide-induced cell death in gastric epithelial cells than gastric cancer cells and the cytoprotective mechanisms might be through decreasing oxidative stress and activating the expression of hemeoxygenase-1 and NADPH quinone oxidoreductase-1.
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Asparaginyl endopeptidase improves the resistance of microtubule-targeting drugs in gastric cancer through IQGAP1 modulating the EGFR/JNK/ERK signaling pathway

Asparaginyl endopeptidase improves the resistance of microtubule-targeting drugs in gastric cancer through IQGAP1 modulating the EGFR/JNK/ERK signaling pathway

Subsequently, we detected the expression of phospho-p38/ p38, phospho-JNK/JNK, and phospho-ERK1/2/ERK1/2 in the groups of normal, NC, and AEP-KO gastric cancer cells because phospho-p38, phospho-JNK, and phospho- ERK1/2 represented the activity of the MAPK kinase pathway. The results showed that the expression levels of phospho-JNK and phospho-ERK1/2, but not phospho-p38, were decreased in AEP-KO gastric cancer cells, while the total levels remained steadfast. The protein level of MDR1 was investigated in these groups as well, and was also decreased in AEP-KO gastric cancer cells (Figure 7A). IQGAP1 is a 190-kDa protein that contains six distinct protein-interacting domains, which are CH (calponin homol- ogy), CC (coiled-coil), WW (domain with two conserved tryptophan residues), IQ1-4 (isoleucine-glutamine), GRD (GTPase-activation-related domain), and RGCT (Ras GAP C-terminus) domains. ERK1/2 is the only identified ligand for the WW domain. EGFR and Rac1/cdc42 interact with IQ and RGCT domains, respectively. Therefore, as Table 2 The expression level of aeP in the serum of gastric
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