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Han S.,Capital Medical University | Han S.,Massachusetts General Hospital | Han S.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | Ma X.,Capital Medical University | And 18 more authors.
Oncotarget | Year: 2016

Gastric cancer is a prevalent tumor that is usually detected at an advanced metastatic stage. Currently, standard therapies are mostly ineffective. Here, we report that Glypican-3 (GPC3) is absent in invasive tumors and metastatic lymph nodes, in particular in aggressive and highly disseminated signet ring cell carcinomas. We demonstrate that loss of GPC3 correlates with poor overall survival in patients. Moreover, we show that absence of GPC3 causes up-regulation of MAPK/FoxM1 signaling and that blockade of this pathway alters cellular invasion. An inverse correlation between GPC3 and FoxM1 is also shown in patient samples. These data identify GPC3 as a potential metastasis suppressor gene and suggest its value as a prognostic marker in gastric cancer. Development of therapies targeting signaling downstream of GPC3 are warranted. Source


Yang Y.-C.,Capital Medical University | Yang Y.-C.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | Cai J.,Capital Medical University | Cai J.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | And 8 more authors.
Carbohydrate Polymers | Year: 2016

In this study, chitosan/heparin immobilized delivery system was developed for the delivery of sorafenib in gastric cancers. The SRF NP was nanosized with spherical outfit and present in the amorphous form. The SRF NP exhibited a sustained release of drug at pH 7.4 conditions and enhanced drug released at pH 5.5 conditions. Flow cytometer analysis showed that cellular uptake of NP increased two-fold after 4 h of incubation compared to 1 h incubation. The SRF NP showed superior anticancer effect compared to that of free SRF in BGC-823 cancer cells. SRF NP induced a remarkable apoptosis of cancer cells consistent with the cytotoxicity assay. Approximately, ∼50% of cell fractions were observed in early apoptosis phase with ∼15% of cells in the late apoptosis stage. Consistently, SRF NP exhibited a strong band for caspase-3 and P-53 than compared to free SRF in MGC-823 cancer cells. Importantly, SRF NP showed superior anticancer effect in xenograft tumor model making it a promising delivery vehicle in the treatment of gastric cancers. © 2015 Elsevier Ltd. Source


Liu L.,Capital Medical University | Bai Z.,Capital Medical University | Bai Z.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | Ma X.,Capital Medical University | And 7 more authors.
Experimental and Therapeutic Medicine | Year: 2016

The present study aimed to evaluate the role of taxol resistance gene 1 (Txr1) in the development of oxali­platin (L-OHP) resistance in gastric cancer (GC). Using SGC-7901 cells as a model, Txr1 was exogenously expressed or knocked down using small interfering RNA. Quantitative polymerase chain reaction (qPCR) and western blotting were performed to establish whether the Txr1 gene is involved in chemoresistance, and cell proliferation was assessed using an MTS assay. To this end, the mRNA and protein levels of Txr1, thrombospondin‑1 and excision repair cross‑complementing 1 protein were measured using qPCR and western blotting, respectively. Txr1‑knockdown significantly increased the sensitivity of the SGC‑7901 cells to L‑OHP, whereas Txr1 overexpression promoted the resistance of the SGC‑7901 cells to L‑OHP. Exogenous Txr1 expression in the SGC‑7901 cells induced L‑OHP resistance, and the siRNA knockdown of Txr1 sensitized the human GC cells to L‑OHP. Txr1 is, therefore, likely to play a role in L‑OHP resistance, acting via TSP1, and should be investigated as a potential therapeutic target in the treatment of GC. © 2016, Spandidos Publications. All Rights reserved. Source


Yang S.,Capital Medical University | Yang S.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | Wu B.,Capital Medical University | Wu B.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | And 9 more authors.
Bioscience Reports | Year: 2016

Tumour suppressor miR-34c deficiency resulted from hyper-methylation in its promoter is believed to be one of the main causes of colorectal cancer (CRC). Till date, miR-34c has been validated as a direct target of p53; but previous evidence suggested other transcription factor(s) must be involved in miR-34c transcription. In the present study, we in the first place identified a core promoter region (-1118 to -883 bp) of pre-miR-34c which was embedded within a hyper-methylated CpG island. Secondly, E2F1 promoted miR-34c transcription by physical interaction with the miR-34c promoter at site -897 to -889 bp. The transcriptional activating effect of E2F1 on miR-34c was in a p53 independent manner but profoundly promoted in the presence of p53 with exposure to 5-aza-2′-deoxycytidine (DAC). Thirdly, stem cell factor (SCF), a miR-34c target, was specifically reduced upon an introduction of E2F1 which lead to suppression of CRC cell proliferation. The E2F1-suppressed cell proliferation was partially abrogated by additional miR-34c inhibitor, indicating that the anti-proliferation effect of E2F1 was probably through activating miR-34c-SCF axis. Finally, SCF/KIT signalling increased E2F1 production by reducing its proteosomal degradation dependent on PI3K/Akt-GSK3β pathway. In conclusion, our results suggested the existence of E2F1-miR-34c-SCF negative feedback loop which was interrupted by the hyper-methylation of miR-34c promoter in CRC cells and increased cell proliferation. © 2016 Authors. Source


Tan J.,Capital Medical University | Tan J.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | Yang S.,Capital Medical University | Yang S.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | And 14 more authors.
Oncotarget | Year: 2015

It was reported that the receptor tyrosine kinase (RTK) family often highly expressed in several mucinous carcinomas. In the present study, we established a murine model of colorectal mucinous adenocardinoma (CRMAC) by treating C57 mice [both wild type (WT) and loss-of-function c-kit mutant type (Wads-/-)] with AOM+DSS for 37 weeks and found that c-kit, a member of RTK family, clearly enhanced the tumor cell proliferation by decreasing p53 and increasing cyclin D1 through AKT pathway. Significantly, c-kit strongly promoted tumor cell invasiveness by increasing ETV4, which induced MMP7 expression and epithelial-mesenchymal transition (EMT) via ERK pathway. In vitro up- or down-regulating c-kit activation in human colorectal cancer HCT-116 cells further consolidated these results. In conclusion, our data suggested that the c-kit signaling obviously promoted proliferation and invasion of CRMAC. Therefore, targeting the c-kit signaling and its downstream molecules might provide the potential strategies for treatment of patients suffering from CRMAC in the future. Source

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