| Background Gastric cancer is a malignant tumor, which threat seriously to the health of human being. The treatments of gastric cancer have surgical therapy, radiation therapy, chemotherapy and biological therapy. Because invasion and metastasis were occur often in gastric cancer, thereby the recurrence is higher after surgical therapy, and the commonly used chemotherapy drugs have side effects and prone to resistance. Invasion, metastasis and multidrug resistances are the significant failure causes of gastric cancer chemotherapy. There is important significance to look for new effective anticancer drugs that can resist to invasion, metastasis, multi-drug resistance to treat gastric cancer. Peroxisome proliferateration-activated receptor gamma (PPARγ) ligand involves in adipocyte differentiation, regulating sugar metabolism, cell cycles, inducing tumor cell differentiation and apoptosis that have antitumor effects. It had been found that PPARγligand troglitazone inhibit the growth of colon cancer cells via inhibiting the expression of NF-kB; Rosiglitazone (ROS) can enhance the effects of 5-Fu inhibiting human liver cancer cells growth. Up to now, effects of ROS on gastric cancer proliferation, invasion and metastasis, multidrug resistance and its mechanism are still unknown.[The role and mechanisms of inhibiting proliferation and induceing apoptosis of human gastric cancer cells]Objective To investigate the effects of ROS on the proliferation and apoptosis and explore the molecule mechanism of apoptosis induced by ROS in human gastric cancer MGC803 cells in vivo and in vitro. Methods and Results The results showed that 12.5μmol/L ROS could inhibit the proliferation of MGC803 cells in a concentration-dependent and time-dependent manner detected by MTT assay and clone formation method. Acridine orange staining and FCM indicated that the apoptosis of MGC803 cells was induced and cell cycle was arrested at G1 stage by ROS in a concentration-dependent manner. Immunocyte chemistry indicated PPARγwas expressed in MGC803 cells. The expression of Bax, PTEN protein increased and bcl-2 protein decreased in MGC803 cells treated with ROS (P<0.05). The MGC803 cells transplanted into subrenal-capsule tumor of mice were inhibited by ROS in a dose-dependent manner. The tumor inhibitory rate was 35.2% with ROS at the dose of 18mg.kg-1. The tumor inhibitory rates were respectively 45.8%, 62.9% with ROS at the dose of 30mg.kg-1 and 50mg/kg, and HE stain indicated tumor cells were metamorphic and parts of tumor cells were apoptosis, and the borderline of the host renal cortex was clean. There were the same tumor inhibition rates at the dose of 30mg.kg-1of ROS (45.8%) and 2mg/kg of MMC (45.5%) in mices. ROS (50mg.kg-1) had no effects on the blood sugar, liver function, renal function. Conlusions ROS could inhibit the proliferation of MGC803 cell in vitro and the growth of MGC803 cells transplanted into subrenal- capsule tumor of Kunming mice in vivo. The mechanism of cell apoptosis was connected with increasing the expression of bax and PTEN protein and decreasing bcl-2 protein in MGC803 cells. ROS had no effects on the blood sugar, liver function, renal function, and their structure of Kunming mice that were transplanted MGC803 cells into subrenal-capsule. Based on the results, the theoretical basis was provided to the feasibility of applying ROS to clinical treatment for gastric cancer.[Rosiglitazone inhibit migration and invasion in gastric cancer cells and its mechanisms]Objects To explore the effects and its molecular mechanisms of ROS on migration and invasion in human gastric cancer SGC7901 and SGC7901/VCR cells. Methods and Results The results showed that the cellular migration and invasion was evidently inhibited after the cells were treated with 40μmol L-1 ROS for 24h by wound healing assay and invasion assay in vitro, which extenuated the expression of MMP-9, uPA, p-ERK1/2, Fra-1 protein and LIMK1, Rac1, Rock, Pak1, cofilin1 protein related to ERK/Fra-1/uPA and Rac1-LIMK1-cofilin1 signal transduction pathway respectively, and increased the expression of TIMP-3 mRNA and protein (P<0.05), and which has no effects on the expression of uPAR mRNA and protein (P>0.05) in SGC7901 and SGC7901/ VCR cells detected by RT-PCR and Western-blot. Conclusions ROS can inhibit significantly migration and invasion in human gastric cancer SGC7901 and SGC7901/VCR cells, the possible mechanism involved in downregulating the expression of p-ERK1/2, Fra-1, uPA and MMP-9 and upregulating TIMP-3 via ERK/Fra-1/uPA pathway, and simultaneously downregulating the expression of Rac1, Rock, Pak1, LIMK1 and p-cofilin1 via Rac1-LIMK1-cofilin1 signal transduction pathway.[Effects of ROS on Vasculogenic Mimicry and Lymphangiogenesis in Nude Mice Human Gastric Cancer Xenograft and its Mechanisms]Objective To investigate the effects of ROS on vascularization mimicry and lymphangiogenesis in nude mice transplanted tumor bearing SGC7901 cells of human gastric cancer, and preliminarily probe into the mechanism of anti- vascularization mimicry and lymphangiogenesis. Methods and Results Results showed that the average weight of Nude Mice in control group and experimental groups was not statistically different before executed (P>0.05). The volume of transplanted tumor was statistical significant lower in the experimental groups than that in the control group (P<0.05), with the elevation of ROS concentration, the rate of inhibitory rate is gradually increasing. The number of vascularization mimicry and lymph vessel in transplanted tumor was significantly decreased in the treatment group compared with control group detected by PAS-CD31 double staining and D2-40 protein staining (P<0.05). The expression of MMP-2, MMP-9, VEGF-C and VEGFR-3 was downregulated and TIMP-2 was upregulated in the treatment group compared with control group by RT PCR and Western blot (P<0.05). Conclusions Rosiglitazone inhibits the growth of transplanted tumor and the formation of vascularization mimicry, lymphangiogenesis in transplanted tumor, and Rosiglitazone affects the formation of vascularization mimicry through down-regulating the expression of MMP-2, MMP-9, up-regulating the expression of TIMP-2, and ROS inhibits tumor lymphangiogenesis through down-regulating the expression of VEGF-C and VEGFR-3, blocking the binding of VEGF-C and its receptor VEGFR-3 in transplanted tumor.[Reversing of Multidrug resistance and the correlative mechanism in SGC7901/VCR cell lines by Rosiglitazone]Objective Based on the results above, we explore that whether Rosiglitazone (ROS) can reverse the resistance to Mitomycin (MMC) of human gastric cancer SGC7901/VCR cell line which has multidrug resistant phenotype in vitro and in vivo, and further explore the possible mechanism of ROS reversing multidrug resistance. Methods and Results The results showed that ROS at 40μM and above had inhibitory effects on the growths of human gastric cancer SGC7901/VCR cell line and its parental generation SGC7901 cell line (P<0.05), and ROS can reverse the resistance to MMC of the human gastric cancer SGC7901/VCR cell line, expressing an obvious dose-dependent relationship by the analysis of cell growth curve and MMT assay. The AO-EB fluorescent staining, flow cytometry and DNA ladder indicated that ROS combined MMC can enhance the apoptosis of SGC7901/VCR cell line in vivo and in vitro. Rosiglitazone could down-regulate the expression of MDR1, p-Akt, Bcl-2 gene and encoding protein P-gp of MDR1 in SGC7901/VCR cell line, and up-regulate Bax gene and its encoding protein in the xenograft tumor by Real time PCR and Western blot. Conclusions To inhibit MDR1/ P-gp pathway and induce apoptosis through the PI3K/Akt signaling pathway maybe the important mechanism of ROS partly reversing the resistance to Mitomycin of human gastric cancer SGC7901/VCR cell line. It can further provide theoretical basis of applying ROS to clinical treatment for gastric cancer, and open a new avenues for gastric cancer treatment.
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