[Show abstract][Hide abstract] ABSTRACT: Alpha-fetoprotein not only serves as a diagnostic marker for liver cancer, but also posses a variety of biological functions. However, the role of Alpha-fetoprotein on tumor angiogenesis and cell invasion remains incompletely understood. In this study, we aimed to evaluate if Alpha-fetoprotein can regulate the major angiogenic factors and matrix metalloproteinases in human liver cancer cells. Alpha-fetoprotein silencing was achieved by Stealth RNAi. Expression of Alpha-fetoprotein was examined by a full-automatic electrochemistry luminescence immunity analyzer. Expression of VEGF, VEGFR-2, MMP-9, and MMP-2 was examined by Western blot and immunocytochemistry. Apoptosis was detected by TUNEL assay. Angiogenesis was detected by in vitro angiogenesis assay kit. Silencing of Alpha-fetoprotein led to an increased apoptosis, which was associated with a decreased expression of vascular endothelial growth factor, vascular endothelial growth factor receptor 2, matrix metalloproteinases-2/9. These results suggest that Alpha-fetoprotein may play a regulatory role on angiogenesis and cell invasion during liver cancer development.
PLoS ONE 02/2014; 9(2):e90660. DOI:10.1371/journal.pone.0090660 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Helicobacter pylori (H. pylori) infection plays an important role in the development of gastric carcinomas. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel human oncoprotein that functions as an important regulator of cell growth and malignant transformation. In the present study, we aimed to investigate the potential mechanisms by which H. pylori upregulates the expression of CIP2A and the functional impact of H. pylori-induced CIP2A in gastric cancer cells. We demonstrated that infection of MKN-45 cells with H. pylori led to a marked increase in the expression of CIP2A at the mRNA and protein levels. H. pylori-induced CIP2A was associated with increased cell proliferation. In addition, H. pylori was found to activate the JNK2 pathway. Importantly, both H. pylori-induced CIP2A production and cell proliferation were partially reversed by inhibition of JNK2 signaling. Similarly, the blockade of H. pylori-induced CIP2A expression by siRNA against CIP2A also inhibited cell proliferation. Thus, H. pylori appears to stimulate the expression of CIP2A and proliferation of gastric cancer cells via JNK2 signaling. These findings suggest that H. pylori-induced upregulation of CIP2A contributes to the development and progression of gastric cancer. Further in vivo studies are warranted to explore the biological role of CIP2A and its interaction with JNK2 signaling in gastric cancer.
International Journal of Molecular Medicine 01/2014; 33(3). DOI:10.3892/ijmm.2014.1615 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim:
Discovering which anticancer drugs attack which organelle(s) of cancer cells is essential and significant, not only for understanding their therapeutic and adverse effects, but also to enable the development of new-generation therapeutics. Here, we show that novel Fe3O4-carboxymethyl cellulose-5-fluorouracil (Fe3O4-CMC-5FU) nanomedicine can apparently enhance the antitumor effect on gastric cancer cells, and its mechanism of killing the SGC-7901 gastric cancer cells can be directly observed at the atomic scale.
Materials & methods:
The novel nanomedicine was prepared using the traditional antitumor drug 5FU to chemically bond onto the functionalized Fe3O4 nanoparticles (Fe3O4-CMC-5FU nanomedicine), and then was fed into SGC-7901 gastric cancer cells. The inorganic Fe3O4 nanoparticles were used to track the distribution and antitumor effect of the nanomedicine within individual SGC-7901 gastric cancer cells.
Results & discussion:
Atomic-level observation and tracking the elemental distribution inside individual cells proved that the magnetic nanomedicine killed the gastric cells mainly by attacking their mitochondria. The enhanced therapeutic efficacy derives from the localized high concentration and poor mobility of the aggregated Fe3O4-CMC-5FU nanomedicine in the cytoplasm.
A brand new mechanism of Fe3O4-CMC-5FU nanomedicine killing SGC-7901 gastric cancer cells by attacking their mitochondria was discovered, which is different from the classical mechanism utilized by traditional medicine 5FU, which kills gastric cancer cells by damaging their DNA. Our work might provide a partial solution in nanomedicines or even modern anticancer medicine for the visualized investigation of their antitumor effect.
[Show abstract][Hide abstract] ABSTRACT: Matrine has potent antitumor activity against a broad variety of cancer cells and our previous study showed that both autophagy and apoptosis were activated during matrine-induced gastric cancer cell death. The aim of the present study was to determine the significance of autophagy in antineoplastic effects of matrine and the molecular mechanism by which matrine induces autophagy in gastric cancer cells. Western blot analysis showed that exposure of gastric cancer cells to matrine resulted in the extent of autophagy increasing in a dose- and time-dependent manner by detecting micro-tubule-associated protein 1 light chain 3 (LC3). This induction was due to activation of autophagic flux, as supported using the lysosome inhibitor, bafilomycin A1, which produced an accumulation of LC3-II. Propidium iodide staining demonstrated that matrine induced cell death in a dose-dependent manner and the autophagy inhibitor 3-methyladenine (3-MA) or bafilomycin A1 enhanced lethality of matrine against gastric cancer cells. Moreover, after pretreatment with 3-MA, some of the gastric cancer cells treated with matrine exhibited prototypical charac-teristics of apoptosis by transmission electron microscopy. The ability of 3-MA to increase matrine-induced apoptosis was further conﬁrmed by Annexin V-FITC/PI staining. Also, the combination of matrine and 3-MA was more potent than matrine alone in inhibiting the proliferation of SGC-7901 cells assessed by sulphorhodamine B assay. Furthermore, administration of the pan-caspase inhibitor zVAD-fmk or autophagy inducer rapamycin decreased the matrine-induced cell death. In addition, matrine treatment did not inhibit the phosphorylation of Akt and its downstream effectors mammalian target of rapamycin (mTOR) as well as p70 ribosomal protein S6 kinase (p70S6K), although the levels of the total Akt and mTOR were decreased. These results suggest that autophagy was activated as a protective mechanism against matrine-induced apoptosis and inhibition of autophagy may be an attractive strategy for enhancing the antitumor potential of matrine in gastric cancer.
International Journal of Oncology 04/2013; 42(4):1417-26. DOI:10.3892/ijo.2013.1817 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this paper, the organic hybrids materials consisting of polarized polymers and small molecules were prepared and the morphology properties were studied by SEM. For CPE/BPSR (60/40) hybrid, the BPSR crystals existed primarily as micro-sized particles, and the particles size distribution was large. The CPE/ZKF (60/40) hybrid was almost in the amorphous state and there was only a small amount of crystallites dispersed in the amorphous phase. Though the interfacial interaction between BPSR particles and CPE matrix was poor, one of the interesting phenomena was observed, when a small amount of BPSR was incorporated into CPE/ZKF hybrid. The domain size of BPSR was dramatically decreased and existed as nano-particles in the CPE/ZKF/BPSR composites. In the case of CPE/ZKF/BPSR composites, the three-dimensional hydrogen-bonding networks could compress and aggregate the molecularly dispersed BPSR into nano-scaled particles.
[Show abstract][Hide abstract] ABSTRACT: A novel organic nanocomposite consisting of chlorinated polyethylene (CPE), 2, 2'-methylene-bis-(4-methyl-6-cyclohexylphenol) (ZKF) and 4, 4'-thio-bis-(3-methy1-6-6tert-butylphenol) (BPSR) was prepared in this article. It was found that the presence of three-dimensional supra-molecular intermolecular hydrogen-bonding interactions was useful to not only compress and aggregate the molecularly dispersed ZKF and BPSR into nano-scaled particles, but also partially block the generated nanoparticles and effectively prevent them from over aggregation into large particles. The DMA results showed that there was a critical concentration for BPSR. When BPSR content was beyond the critical value, a novel loss peak was observed because of the formation of ZKF-BPSR-rich phase. These may imply that CPE/ZKF/BPSR nanocomposites possessing both high loss peak and controllable loss peak position can be more efficient in damping performance.
[Show abstract][Hide abstract] ABSTRACT: In this paper, the multi-layered gradient materials consisting of polarized polymers and small molecules were prepared and the damping properties were studied by DMA. The predicted and experimental results showed that, it was possible to obtain damping material with broad efficient damping range by two-layered hybrid materials, the value in the middle of two peaks could be improved by increasing the number of layers of the multi-layered hybrids and there was a higher minimum value. On the other hand, with increased number of the layers of the multi-layered hybrid materials, the temperature dependence of tan 8 could be improved. For five-layered gradient materials, it was almost rectangular transition range with values for the area under the linear tan delta curve. Thus, it would be feasible in theory and experiment to broaden the efficient damping range by multi-layered gradient materials based on organic hybrids, which provided a new approach and solid basis for developing high performance damping materials with a broad and high damping range.
[Show abstract][Hide abstract] ABSTRACT: A theoretical study on damping properties of multi-layered hybrid materials was presented with the aim to obtain good damping materials with a broad and high damping range. The value of the multi-layered organic hybrid materials consisting of polarized polymers and small molecules was evaluated via the correspondence principle. Similarly, the damping properties of the multi-layered organic hybrid materials were predicted according to our previous work. With increasing the number of the layers of multi-layered hybrids, the temperature dependence of could be improved and it was almost rectangular transition range with values for the area under the linear curve. Therefore, it could be considered to be a new approach to improve the temperature dependence of the damping materials and obtain good damping materials with a broad and high damping range.
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common internal malignant tumors. Glypican-3 (GPC3) is involved in the biological and molecular events in the tumorigenesis of HCC. We used RNA interference to evaluate the molecular effects of GPC3 suppression at the translational level and demonstrated for the first time that GPC3 silencing results in a significant elevation of the Bax/Bcl-2 ratio, the release of cytochrome c from mitochondria and the activation of caspase-3. The results suggest that GPC3 regulates cell proliferation by enhancing the resistance to apoptosis through the dysfunction of the Bax/Bcl-2/cytochrome c/caspase-3 signaling pathway and therefore plays a critical role in the tumorigenesis of HCC. Thus, the knockdown of GPC3 should be further investigated as an attractive novel approach for the targeted gene therapy of HCC.
Biochemical and Biophysical Research Communications 02/2012; 419(4):656-61. DOI:10.1016/j.bbrc.2012.02.069 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1), a protein involved in the DNA repair mechanism, plays an important role in carcinogenesis. In this study, we investigated whether single nucleotide polymorphisms of PARP1 contribute to gastric cancer (GC) and its precursor lesions (gastric precancerous lesions; GPL) in a case-control study conducted in the Hexi area of China, a high-risk area for GC.
PARP1 162C>G (Phe54Leu) and 2819A>G (Lys940Arg) polymorphisms were genotyped by real-time PCR using a TaqMan assay in 140 GC cases, 110 GPL cases, and 120 controls. Data were statistically analyzed using the chi-squared test and a logistic regression model.
The presence of the PARP1 2819G allele was associated with an increased risk of GC (odds ratio [OR] 2.354; 95% CI 1.140, 4.861; p = 0.018), especially for cardia GC and diffuse-type GC (ORs 2.988 and 3.784, respectively). We also observed an interaction between Helicobacter pylori infection, GC family history, and the presence of the PARP1 2819G allele. In contrast, the PARP1 162C>G polymorphism was not significantly associated with GPL or GC.
The study suggests that the PARP1 2819G allele is associated with an increased risk of GC. In addition, H. pylori-positive status and family history jointly contribute to a higher risk of GC.
[Show abstract][Hide abstract] ABSTRACT: In Hexi area of Gansu Province, people have a higher susceptibility of gastric cancer than people in the rest area of China. There is substantial geographic variation in the incidence of gastric cancer. In this article, the present author explored the roles of H. pylori infection and IL-10 promoter polymorphisms in development of gastric cancer in this area. A total of 304 participants were admitted to our study, and they were divided into two groups: control group and case group. Blood samples from all subjects were collected for gene extraction using DNA extraction kits. IL-10 polymorphisms were determined by SNaPshot Multiplex. To test H. pylori infection and its typing H. pylori antibody Immunoblotting Kits were used. This research suggested that environmental factor played an important role in the pathogenesis of gastric carcinoma in the area, H. pylori infection increased the risk of gastric cancer (OR = 2.612, 95% CI 1.636-4.170) and subject with H. pylori I-type positive was at significantly higher risk for progression to gastric cancer (OR = 4.712, 95% CI 2.656-8.537). For subjects with the ATA/GCC or GCC/GCC haplotype of the IL-10-1082/-819/-592 polymorphism relative to the ATA/ATA haplotype group, the risk of gastric cancer development was significantly increased. It has been demonstrated that the presence of IL-10-819 C alleles and IL-10-592 C alleles was associated with an increased risk for gastric cancer development in H. pylori-infected patients and IL-10 promoter polymorphisms and H. pylori have a synergistic effect on gastric cancer in Hexi population.
[Show abstract][Hide abstract] ABSTRACT: Matrine has a wide range of pharmacological effects including antitumor activity in vitro and in vivo. Autophagy is closely associated with tumors and plays an important role in human tumor suppression, so inducing autophagy is a potential therapeutic strategy in adjuvant chemotherapy. The aim of this study was to investigate whether or not autophagy is involved in antitumor effects of matrine on human gastric cancer SGC-7901 cells, and to further elucidate the underlying molecular mechanisms. Sulphorhodamine B (SRB) assay was used to examine matrine's cytotoxicity against SGC-7901 gastric cancer cells. The effects of matrine on the cell cycle and apoptosis were measured by ﬂow cytometry, and cellular morphology was observed under an inverted phase contrast microscope and transmission electron microscope. Monodansylcadaverine (MDC) staining was used to detect autophagy. The expression levels of Bax and Beclin 1 in SGC-7901 cells were monitored by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that matrine signiﬁcantly inhibited the proliferation of SGC-7901 gastric cancer cells and induced G1-phase cell cycle arrest. Furthermore, both autophagy and apoptosis were activated during the matrine-induced death of SGC-7901 cells. Beclin 1 is involved in matrine-induced autophagy and the pro-apoptotic mechanisms of matrine may be associated with its up-regulation of Bax expression. These ﬁndings indicate that matrine is a potent antitumor agent for treating gastric cancer. The ability of matrine to induce autophagy underlines its potential utility as a new gastric cancer treatment modality.
[Show abstract][Hide abstract] ABSTRACT: Autophagy is an intracellular lysosome-dependent catabolic process that is indispensable for maintaining cellular homeostasis through the turnover and elimination of defective or redundant proteins and damaged or aged organelles. Recent studies suggest that autophagy may be closely associated with tumorigenesis and the response of tumor cells to chemotherapeutic drugs. This article reviews recent advances in understanding the molecular mechanisms underlying the regulation of autophagy and the role of autophagy in oncogenesis and anticancer therapy. It is paradoxical that autophagy acts as a mechanism for tumor suppression and contributes to the survival of tumors. In addition, whether autophagy in response to chemotherapies results in cell death or instead protects cancer cells from death is complicated, depending on the nature of the cancer and the drug.
The American Journal of the Medical Sciences 06/2011; 343(2):155-61. DOI:10.1097/MAJ.0b013e31821f978d · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PI3K/AKT constitutes an important pathway regulating the signaling of multiple biological processes and plays a critical role in carcinogenesis. PIK3CA gene missense mutations have been reported in many human cancer types. The mutation of it in hepatocellular carcinoma cases varies with different races and regions. In this study, we investigated PIK3CA mutation in Chinese hepatocellular carcinoma patients. A total 90 Chinese patients of hepatocellular carcinoma were recruited in this study. Exons 9 and 20 hotspots mutations of PIK3CA gene were detected by PCR-based DNA sequencing. Two point mutations (E542K and D549H) in exon 9 were found in only one patient (1/90; 1.11%), no mutation was found in exon 20 in any cases. 57 patients are associated with HBV infection (57/90; 63.3%), and 8 patients with HCV infection (8/90; 8.9%). The frequency of the PIK3CA mutations in hepatocellular carcinoma seems to be lower in Chinese hepatocellular carcinoma patients. These findings suggest that PI3K mutations may not play a major role in hepatic carcinogenesis in Chinese. HBV infection has close relationship with HCC in Chinese.
[Show abstract][Hide abstract] ABSTRACT: The roles of reactive oxygen species (ROS) and mitochondrial damage in the cadmium (Cd)-induced injury of liver cells were studied by using N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine hydrochloride (ALCAR). After exposure of experimental rats to cadmium (Cd) for 16 h, mitochondrial membrane potential (MMP), ROS production, glutathione peroxidase (GSH-Px) activity, glutathione (GSH) content, malondialdehyde (MDA) content and DNA single-strand break (DNA-SSB) were analyzed. Loss of MMP, increase of ROS production, inhibition of GSH-Px activity, elevation of GSH content, rise of MDA content and DNA-SSB level suggest the participation of ROS and mitochondrion in Cd-induced injury of liver cell. NAC pretreatment attenuated oxidative stress, reversed the decline in GSH-Px activity and reduced GSH and MDA levels significantly. However, Cd-induced loss in MMP was significantly exacerbated by NAC. For another, ALCAR did not perform as well as NAC in terms of reducing ROS production, restoring GSH-Px activity and reducing GSH content. Nevertheless, it significantly improved the recovery of MMP and reduction of MDA content. In addition, conspicuous DNA damage was observed in the samples treated with NAC or ALCAR, indicating Cd could attack DNA through other pathways. These results suggest that oxidative stress or mitochondrial impairment plays a main role in different injuries respectively.
Toxicology and Industrial Health 12/2010; 27(3):249-56. DOI:10.1177/0748233710386408 · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cyclo-oxygenase-2 (COX-2, also known as prostaglandin synthase 2) influences carcinogenesis through regulation of angiogenesis, apoptosis, and cytokine expression. COX-2 is encoded by the gene PTGS2. Several studies have suggested that PTGS2 single-nucleotide polymorphisms (SNPs) are involved in gastrointestinal carcinogenesis. In this study, we observed the PTGS2 Val511Ala (5939T/C) polymorphism in the Chinese population for the first time, and investigated whether this polymorphism might contribute to gastric cancer in a case-control study conducted in the Gansu province of China, a high-risk area for gastric cancer.
We determined the genotypes of 110 gastric cancer patients and 138 controls using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) analysis. Data were statistically analyzed using a chi-squared test and a logistic regression model.
In our analysis, PTGS2 5939C allele carriers were at increased risk of gastric cancer (odds ratio [OR] 1.742; 95% confidence interval [CI] 1.009, 3.005; p = 0.045). We also found an interaction between Helicobacter pylori infection, a family history of gastric cancer, and presence of the 5939C allele. This study further indicated that H. pylori-positive status and family history jointly contribute to a higher risk of gastric cancer.