CTCF-activated SNHG16 facilitates gastrointestinal stromal tumor by targeting miR-128-3p/CASC3 axis.

In this study, it was ascertained that SNHG16 was up-regulated in gastrointestinal stromal tumor (GIST) tissues and cells, and was responsible for the aggravated malignant behaviors of GIST cells. CTCF served as a transcription activator responsible for the overexpression of SNHG16 in GIST cells. MiR-128-3p was negatively regulated by SNHG16 and exerted anti-tumor effects. Moreover, CASC3 was the direct target mRNA of miR-128-3p, through which miR-128-3p exerted function influence on GIST cell malignant behaviors. SNHG16 competitively bound with miR-128-3p against CASC3, thus positively regulating CASC3 expression. Finally, functional assays carried out in vitro proved SNHG16 could modulate GIST cell proliferation, migration, invasion and apoptosis via miR-128-3p/CASC3 axis. Animal experiments were also designed and implemented in a rescue way and evidenced that up-regulation of CASC3 countervailed the inhibitory impacts of SNHG16 silence on the progression of GIST. In summary, SNHG16 up-regulated by CTCF facilitated the progression of GIST through miR-128-3p/CASC3.

A Conservative Memristive Chaotic System with Extreme Multistability and Its Application in Image Encryption.

In this work, a novel conservative memristive chaotic system is constructed based on a smooth memristor. In addition to generating multiple types of quasi-periodic trajectories within a small range of a single parameter, the amplitude of the system can be controlled by changing the initial values. Moreover, the proposed system exhibits nonlinear dynamic characteristics, involving extreme multistability behavior of isomorphic and isomeric attractors. Finally, the proposed system is implemented using STMicroelectronics 32 and applied to image encryption. The excellent encryption performance of the conservative chaotic system is proven by an average correlation coefficient of 0.0083 and an information entropy of 7.9993, which provides a reference for further research on conservative memristive chaotic systems in the field of image encryption.

A Simple Parallel Chaotic Circuit Based on Memristor.

This paper reports a simple parallel chaotic circuit with only four circuit elements: a capacitor, an inductor, a thermistor, and a linear negative resistor. The proposed system was analyzed with MATLAB R2018 through some numerical methods, such as largest Lyapunov exponent spectrum (LLE), phase diagram, Poincaré map, dynamic map, and time-domain waveform. The results revealed 11 kinds of chaotic attractors, 4 kinds of periodic attractors, and some attractive characteristics (such as coexistence attractors and transient transition behaviors). In addition, spectral entropy and sample entropy are adopted to analyze the phenomenon of coexisting attractors. The theoretical analysis and numerical simulation demonstrate that the system has rich dynamic characteristics.

A Hidden Chaotic System with Multiple Attractors.

This paper reports a hidden chaotic system without equilibrium point. The proposed system is studied by the software of MATLAB R2018 through several numerical methods, including Largest Lyapunov exponent, bifurcation diagram, phase diagram, Poincaré map, time-domain waveform, attractive basin and Spectral Entropy. Seven types of attractors are found through altering the system parameters and some interesting characteristics such as coexistence attractors, controllability of chaotic attractor, hyperchaotic behavior and transition behavior are observed. Particularly, the Spectral Entropy algorithm is used to analyze the system and based on the normalized values of Spectral Entropy, the state of the studied system can be identified. Furthermore, the system has been implemented physically to verify the realizability.

LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop contributes to the proliferation of gastric cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) are increasingly investigated in numerous carcinomas containing gastric cancer (GC). The aim of our research is to inquire about the expression profile and role of LBX2-AS1 in GC. METHODS: The expressions of LBX2-AS1, miR-219a-2-3p, FUS and LBX2 were measured by qRT-PCR. Western blot evaluated FUS and LBX2 protein levels. Cell proliferation and apoptosis were, respectively, evaluated by CCK-8, colony formation, EdU, flow cytometry and TUNEL assays. FISH and subcellular fractionation assays examined the position of LBX2-AS1. The binding between genes were certified by RIP, RNA pull-down, ChIP and luciferase reporter assays. Pearson correlation analysis analyzed the association of genes. Kaplan-Meier method detected the relationship of LBX2-AS1 expression with overall survival. RESULTS: The up-regulation of LBX2-AS1 in GC tissues and cells was verified. Function assays proved that LBX2-AS1 down-regulation restricted the proliferation ability. Then, we unveiled the LBX2-AS1/miR-219a-2-3p/FUS axis. Additionally, LBX2-AS1 positively regulated LBX2 mRNA stability via FUS. LBX2 transcriptionally modulated LBX2-AS1. In the end, rescue and in vivo experiments validated the whole regulatory mechanism. CONCLUSION: LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop mainly affected the proliferation and apoptosis abilities of GC cells, offering novel therapeutic targets for the treatment of patients with GC.

SAV1, regulated by microRNA-21, suppresses tumor growth in colorectal cancer.

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

Small nucleolar RNA host gene 1 promotes development and progression of colorectal cancer through negative regulation of miR-137.

Small nucleolar RNA host gene 1 (SNHG1) is critical in the progression of cancers. However, the mechanism by which SNHG1 regulates the progression of colorectal cancer (CRC) remains unclear. Expressions of SNHG1 and miR-137 in CRC tissues and cell lines were evaluated by quantitative real-time polymerase chain reaction. A luciferase reporter gene assay was conducted to investigate miR-137 target. Additionally, RNA pull-down assay was performed to explore the physical association between miR-137, SNHG1, and RNA induced silencing complex (RISC). Cell cycling and invasion were examined by flow cytometry (FCM) and transwell assays. The in vivo carcinogenic activity of SNHG1 was examined using murine xenograft models. Expression of RICTOR, serine/threonine kinase 1 (AKT), serum and glucocorticoid-inducible kinase 1 (SGK1), p70S6K1, and LC3II/LC3I ratio was examined by Western blot analysis. SNHG1 upregulation was observed in CRC tissues and cell lines, which was associated with the lymph node metastasis, advanced TNM stage and poorer prognosis. SNHG1 increased RICTOR level in CRC via sponging miR-137. In addition, SNHG1 silencing inhibited CRC cell proliferation and migration in vitro and in vivo. SNHG1 regulated RICTOR expression by sponging miR-137 and promoted tumorgenesis in CRC.

Dynamics and Entropy Analysis for a New 4-D Hyperchaotic System with Coexisting Hidden Attractors.

This paper presents a new no-equilibrium 4-D hyperchaotic multistable system with coexisting hidden attractors. One prominent feature is that by varying the system parameter or initial value, the system can generate several nonlinear complex attractors: periodic, quasiperiodic, multiple topology chaotic, and hyperchaotic. The dynamics and complexity of the proposed system were investigated through Lyapunov exponents (LEs), a bifurcation diagram, a Poincaré map, and spectral entropy (SE). The simulation and calculation results show that the proposed multistable system has very rich and complex hidden dynamic characteristics. Additionally, the circuit of the chaotic system is designed to verify the physical realizability of the system. This study provides new insights into uncovering the dynamic characteristics of the coexisting hidden attractors system and provides a new choice for nonlinear control or chaotic secure communication technology.

Adaptive Synchronization Strategy between Two Autonomous Dissipative Chaotic Systems Using Fractional-Order Mittag-Leffler Stability.

Compared with fractional-order chaotic systems with a large number of dimensions, three-dimensional or integer-order chaotic systems exhibit low complexity. In this paper, two novel four-dimensional, continuous, fractional-order, autonomous, and dissipative chaotic system models with higher complexity are revised. Numerical simulation of the two systems was used to verify that the two new fractional-order chaotic systems exhibit very rich dynamic behavior. Moreover, the synchronization method for fractional-order chaotic systems is also an issue that demands attention. In order to apply the Lyapunov stability theory, it is often necessary to design complicated functions to achieve the synchronization of fractional-order systems. Based on the fractional Mittag-Leffler stability theory, an adaptive, large-scale, and asymptotic synchronization control method is studied in this paper. The proposed scheme realizes the synchronization of two different fractional-order chaotic systems under the conditions of determined parameters and uncertain parameters. The synchronization theory and its proof are given in this paper. Finally, the model simulation results prove that the designed adaptive controller has good reliability, which contributes to the theoretical research into, and practical engineering applications of, chaos.

Bradykinin Promotes Cell Proliferation, Migration, Invasion, and Tumor Growth of Gastric Cancer Through ERK Signaling Pathway.

Bradykinin (BK) has been reported to be involved in the progression of diverse types of cancer. In the present study, we investigated the possible role of BK in cell proliferation, migration, invasion, and tumor growth of gastric cancer (GC). Cell proliferation was evaluated by MTT assays. Cell migration and invasion were assessed by Transwell assays. Tumor growth of nude mice was detected by establishing subcutaneous xenograft tumor model. Silencing of bradykinin B1 receptor (B1R) and the bradykinin B2 receptor (B2R) was performed by transfecting cells with si-B1R and si-B2R, respectively. The protein expression levels of phospho-ERK1/2 (p-ERK1/2), matrix metalloproteinase (MMP)-2, MMP-9, and E-Cadherin were examined by Western blot. Data revealed that BK promoted cell proliferation, migration, invasion, and the in vivo tumor growth of GC cells SGC-7901 and HGC-27. Furthermore, BK elevated the protein levels of p-ERK1/2, MMP-2, and MMP-9, but reduced E-Cadherin. In addition, by repressing B2R using si-B2R or inhibiting ERK signaling pathway using PD98059, BK-mediated promotion of cell proliferation, migration, and invasion and upregulation of p-ERK1/2, MMP-2/9, as well as downregulation of E-Cadherin were attenuated. Taken together, the present study demonstrated that BK promoted cell proliferation, migration, invasion, and tumor growth by binding to B2R via ERK signaling pathway. Our findings may provide promising options for the further treatment of GC. J. Cell. Biochem. 118: 4444-4453, 2017. © 2017 Wiley Periodicals, Inc.

The long non-coding RNA TUG1 indicates a poor prognosis for colorectal cancer and promotes metastasis by affecting epithelial-mesenchymal transition.

BACKGROUND: Long intergenic non-coding RNAs (lncRNAs) are a class of non-coding RNAs that are involved in gene expression regulation. Taurine up-regulated gene 1 (TUG1) is a cancer progression related lncRNA in some tumor oncogenesis; however, its role in colorectal cancer (CRC) remains unclear. In this study, we determined the expression patterns of TUG1 in CRC patients and explored its effect on CRC cell metastasis using cultured representative CRC cell lines. METHODS: The expression levels of TUG1 in 120 CRC patients and CRC cells were determined using quantitative real-time PCR. HDACs and epithelial-mesenchymal transition (EMT)-related gene expression were determined using western blot. CRC cell metastasis was assessed by colony formation, migration assay and invasion assay. RESULTS: Our data showed that the levels of TUG1 were upregulated in both CRC cell lines and primary CRC clinical samples. TUG1 upregulation was closely correlated with the survival time of CRC patients. Overexpression of TUG1 in CRC cells increased their colony formation, migration, and invasion in vitro and promoted their metastatic potential in vivo, whereas knockdown of TUG1 inhibited the colony formation, migration, and invasion of CRC cells in vitro. It is also worth pointing out that TUG1 activated EMT-related gene expression. CONCLUSION: Our data suggest that tumor expression of lncRNA TUG1 plays a critical role in CRC metastasis. TUG1 may have potential roles as a biomarker and/or a therapeutic target in colorectal cancer.

Silencing of FGFR4 could influence the biological features of gastric cancer cells and its therapeutic value in gastric cancer.

To clarify the role of fibroblast growth factor receptor 4 (FGFR4) in gastric cancer (GC) and explore the therapeutic value of BGJ398 targeted to FGFR4. We constructed lentivirus vectors to stably knockdown FGFR4 expression in GC cells. Function assays in vitro and in vivo, treated with 5-fluorouracil (5-Fu) and BGJ398, were performed to study the change of biological behaviors of GC cells and related mechanism. The proliferation and invasive ability of HGC27 and MKN45 significantly decreased while the apoptosis rate of GC cells obviously increased in shRNA group (P < 0.05). The expressions of Bcl-xl, FLIP, PCNA, vimentin, p-erk, and p-STAT3 significantly reduced while the expressions of caspase-3 and E-cadherin markly enhanced in shRNA group. The proliferation abilities of GC cells were more significantly inhibited by the combination of BGJ398 and 5-Fu in shRNA group (P < 0.05). Compared to negative control (NC), the single and combination of 5-Fu and BGJ398 all significantly increased the apoptosis rate of GC cells, especially in the combination group (P < 0.01). The single and combination of 5-Fu and BGJ398 decreased the expressions of PCNA, Bcl-xl, and FLIP while increased the expression of caspase-3 in GC cells, especially in shRNA groups. Furthermore, knockdown of FGFR4 expression might prevent the growth of GC in vivo. Silencing of FGFR4 expression could weaken the invasive ability, increase the apoptosis rate, and decrease the proliferation ability of GC cells in vitro and in vivo. Furthermore, the combination of 5-Fu and BGJ398 had synergy in inhibiting the proliferation ability and increasing apoptosis rate of GC cells, directing a new target drug in GC.

The over-expression of FGFR4 could influence the features of gastric cancer cells and inhibit the efficacy of PD173074 and 5-fluorouracil towards gastric cancer.

The aim was to investigate the function of fibroblast growth factor receptor 4 (FGFR4) in gastric cancer (GC) and explore the treatment value of agent targeted to FGFR4. Function assays in vitro and in vivo were performed to investigate the discrepancy of biological features among the GC cells with different expression of FGFR4. GC cells were treated with the single and combination of PD173074 (PD, an inhibitor of FGFR4) and 5-fluorouracil (5-Fu). The invasion ability were stronger, and the apoptosis rates were lower in MGC803 and BGC823 cells treated with FGFR4-LV5 (over-expression of FGFR4 protein) (P < 0.05). The proliferation ability of GC cells is reduced when treated by the single and combination of 5-Fu and PD while that of the FGFR4-LV5 group was less inhibited compared with control group (P < 0.05). The apoptosis rates are remarkably increased in GC cells treated with the single and combination of 5-Fu and PD (P < 0.05). However, the apoptosis rate obviously is reduced in GC cells treated with FGFR4-LV5 compared with control group (P < 0.05). The expression of PCNA and Bcl-XL is remarkably decreased, and the expression of Caspase-3 and cleaved Caspase-3 is obviously increased in GC cells treated with the single and combination of 5-Fu and PD. The tumor volumes of nude mice in FGFR4-LV5 group were much more increased (P < 0.05). The over-expression of FGFR4 enhanced the proliferation ability of GC in vitro and in vivo. The combination of 5-Fu and PD exerted synergetic effect in weakening the proliferation ability and promoting apoptosis in GC cells, while the over-expression of FGFR4 might inhibit the efficacy of two drugs.

The role of microRNA-1274a in the tumorigenesis of gastric cancer: accelerating cancer cell proliferation and migration via directly targeting FOXO4.

MicroRNAs (miRNAs) are a series of 18-25 nucleotides length non-coding RNAs, which play critical roles in tumorigenesis. Previous study has shown that microRNA-1274a (miR-1274a) is upregulated in human gastric cancer. However, its role in gastric cancer progression remains poorly understood. Therefore, the current study was aimed to examine the effect of miR-1274a on gastric cancer cells. We found that miR-1274a was overexpressed in gastric cancer tissues or gastric cancer cells including HGC27, MGC803, AGS, and SGC-7901 by qRT-PCR analysis. Transfection of miR-1274a markedly promoted gastric cancer cells proliferation and migration as well as induced epithelial-mesenchymal transition (EMT) of cancer cells. Our further examination identified FOXO4 as a target of miR-1274a, which did not influence FOXO4 mRNA expression but significantly inhibited FOXO4 protein expression. Moreover, miR-1274a overexpression activated PI3K/Akt signaling and upregulated cyclin D1, MMP-2 and MMP-9 expressions. With tumor xenografts in mice models, we also showed that miR-1274a promoted tumorigenesis of gastric cancer in vivo. In all, our study demonstrated that miR-1274a prompted gastric cancer cells growth and migration through dampening FOXO4 expression thus provided a potential target for human gastric cancer therapy.

MiR-218 regulates cisplatin chemosensitivity in breast cancer by targeting BRCA1.

Cisplatin resistance presents a major challenge in the successful treatment of breast cancer, and its mechanism has not been documented well. In this study, to determine the relationship between chemotherapy resistance and microRNA (miRNA) expression during the development of cisplatin resistance in breast cancer, we used microRNA microarrays analysis successfully identified 19 miRNAs that were either overexpressed or underexpressed (8 upregulated and 11 downregulated) in the MCF-7 cell line and its cisplatin-resistant variant MCF-7/DDP. Among them, the miR-218 was most downregulated in cisplatin-resistant cell lines and identified that breast cancer 1 (BRCA1) was the cellular targets of miR-218. In vivo assay also demonstrated that restoring miR-218 expression in MCF-7/DDP cell line could sensitize cells against cisplatin, thereby increasing cisplatin-mediated tumor cell apoptosis and reducing DNA repair. Kaplan-Meier survival analysis indicated that patients with breast cancer display high levels of miR-218 and low levels of BRCA1 expression; these patients may gain the greatest benefits in terms of increased survival when treated with cisplatin. All of these results indicated that miR-218 has a significant function in the development of cisplatin resistance in breast cancer. Restoring miR-218 expression may constitute a novel therapeutic approach by which to increase cisplatin sensitivity in breast cancer.

Hypoxia-inducible factor-1α C1772T polymorphism and cancer risk: a meta-analysis including 18,334 subjects.

Studies on HIF 1α C1772T (P582S) polymorphism revealed a genetic susceptibility to malignant tumors, however, the results were conflicting. We conducted a meta-analysis utilizing 29 eligible case-control studies to analyze the data concerning the association between the HIF-1α C1772T polymorphism and cancer risks. There was statistical association between the HIF-1α CT/TT genotype and cancer risk (OR = 1.28, 95% CI = 1.06-1.54, P(heterogeneity) < .00001). The stability of these observations was confirmed by a one-way sensitivity analysis. Our findings suggested that CT/TT genotype was associated with increased risks of prostate cancer. Besides, the HIF-1α C1772T polymorphism most likely contributes to susceptibility to malignant tumors, especially in American population.

Study on effect of the expression of siRNA in gastric cancer bearing nude mice transplanted tumor NEDD9 gene.

The clinical study found that NEDD9 showed high expression on the invasion in gastric cancer tissues and metastasis of the tumor. Based on promoting the fundamental role (Sisen et al., 2013) to the expression level, the author further study NEDD9 siRNA, which could significantly reduce NEDD9 protein and mRNA in gastric cancer BGC823 cells, inhibition of cell proliferation, induce cell apoptosis, and decrease the invasiveness of gastric cancer cells, suggesting that NEDD9 plays an important role in the gastric cancer cell proliferation, apoptosis and invasion force. Through constructing a model transplanted gastric cancer in nude mice, the author observes the effect of NEDD9 siRNA on the growth of gastric cancer x-engrafts, and application of NEDD9 immunohistochemical SP method. The author also uses Western blot method to detect the gastric carcinoma in nude mice transplanted tumor tissues expression; applies situ hybridization, RT-PCR technology to detect the gastric cancer engraft tissues in NEDD9 mRNA. In order to further explore the relationship between NEDD9 and the development of gastric cancer, he provides a theoretical basis for the NEDD9 targeted therapy.

The correlations between the expression of FGFR4 protein and clinicopathological parameters as well as prognosis of gastric cancer patients.

BACKGROUND: Fibroblast growth factor receptor 4 (FGFR4) was seldom investigated in gastric cancer (GC). The purpose of the study was to elucidate the expression of FGFR4 protein in GC and related clinical significance. METHODS: Ninety-four paraffin-embedded tumor specimens were obtained from Cancer Hospital, Fudan University. The expression of FGFR4 as well as p53, p21, EGFR, neu, c-myc, and PCNA were detected by immunohistochemical method. Then, correlation analysis and survival analysis were performed. RESULTS: The expression rate of FGFR4 protein in GC tissues and normal stomach tissues was 93.6% and 30.8%, respectively (P = 0.000). The expression of FGFR4 was positively correlated with the expression of p21, neu and PCNA (P-value was 0.009, 0.012, and 0.018, respectively). Subgroup analysis showed that compared to low expression group, the prognosis of patients with III/IV stage and negative expression of p21 in high expression group of FGFR4 were worse (P = 0.048, 0.041, respectively). Multivariate analysis showed that TNM stage was the independent prognostic factor in high expression group (HR, 11.593; 95% CI, 3.532-18.058; P = 0.000). CONCLUSIONS: High expression of FGFR4 protein, accelerating the progression of advanced GC, might be associated with a poor prognosis in patients with advanced FC.