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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.


Li Q.,CapitalMedical University | Li Q.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | Li Q.,Shanxi Medical University | Wang J.,Shanxi Medical University | And 4 more authors.
Japanese Journal of Clinical Oncology | Year: 2016

Objective: Laparoscopy-assisted gastrectomy for advanced gastric cancer still remains controversial. The aim of this study is to compare oncologic feasibility and technical safety of laparoscopic versus open gastrectomy for advanced gastric cancer with D2 lymphadenectomy by comparing patients' short-term postoperative outcomes. Methods: One hundred and one patients with laparoscopy-assisted gastrectomy and 101 patients with open gastrectomy were one-to-one matched and then compared in terms of operative outcomes and hospital courses. Results: The laparoscopic group showed significantly longer operating time (297.4 vs. 198.1 min, P < 0.001), earlier first flatus time (2.8 vs. 3.6 days, P < 0.001), earlier diet start time (3.8 vs. 4.6 days, P < 0.001), shorter hospital stay (10.5 vs. 11.9 days, P < 0.001) and lessmorbidity (21.8 vs. 37.6%, P=0.019). However, retrieval lymph nodes, intraoperative blood loss, transfused patients, postoperative fever and mortality were similar in the two groups. As for complications, incision infection (1.0 vs. 8.9%, P=0.021) was significantly more common in the open group than in the laparoscopic group. In the subgroup comparisons of outcomes of laparoscopy-assisted gastrectomy, the tumor, node,metastasis III group showed significantly increased retrieval lymph nodes (37.2 vs. 31.0, P < 0.001), increased intraoperative blood loss (147.2 vs. 120.5 ml, P = 0.010), increased length of hospital stay (11.1 vs. 9.9 days, P < 0.001) and increased morbidity (32.6 vs. 13.8%, P = 0.024) when compared with the tumor, node, metastasis II group. Conclusions: Laparoscopy-assisted gastrectomy is feasible and safe for the treatment of advanced gastric cancer with D2 lymphadenectomy compared with open gastrectomy. Higher-level tumor stage (tumor, node, metastasis III) may increase the operative risk and should be performed with caution by surgeons with considerable experience of laparoscopic gastrectomy. © The Author 2016.


Yang S.,Capital Medical University | Yang S.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | Li W.,Capital Medical University | Li W.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research | And 15 more authors.
BMC Cancer | Year: 2015

Background: Silence of the tumor suppressor miR-34c is implicated in the development of colorectal cancer (CRC). For the past few years, Resveratrol (Res) has been introduced to oncotherapies alone or with traditional chemotherapeutic drugs. However, the study of molecular mechanism involved in the anti-CRC effect of Res is still ongoing. Methods: The anti-CRC effect of Res alone or with Oxaliplatin (Oxa) was determined by cell viability assay, soft agar colony formation assay, flow cytometry and real-time cellular analyzer in HT-29 (p53 +) and HCT-116 (p53 -) CRC cell lines. Expressions of miR-34c and its targets were detected by qPCR and/or western blot. To evaluate the role of miR-34c in anti-CRC effect by Res alone or with Oxa, miR-34c was up or down-regulated by lentiviral mediation or specific inhibitor, respectively. To investigate how miR-34c was increased by Res, the methylation status of miR-34c promoter was detected by MSP. The tumor bearing mouse model was established by subcutaneous injection of HCT-116 cells to assess anti-CRC effect of Res alone or with Oxa in vivo. IL-6 and TNF-α in xenografts were detected by ELISA. Results: Res inhibited cell viability, proliferation, migration and invasion as well as promoted apoptosis both in HT-29 and HCT-116 CRC cells. The anti-CRC effect of Res was partially but specifically through up-regulating miR-34c which further knocked down its target KITLG; and the effect was enhanced in the presence of p53 probably through inactivating PI3K/Akt pathway. Besides, Res sensitized CRC cells to Oxa in a miR-34c dependent manner. The xenograft experiments showed that exposure to Res or Oxa suppressed tumor growth; and the efficacy was evidently augmented by the co-treatment of Res and Oxa. Likewise, miR-34c level was elevated in xenografts of Res-treated mice while the KITLG was decreased. Finally, Res clearly reduced IL-6 in xenografts. Conclusion: Res suppressed CRC by specifically activating miR-34c-KITLG in vitro and in vivo; and the effect was strengthened in the presence of p53. Besides, Res exerted a synergistic effect with Oxa in a miR-34c dependent manner. We also suggested that Res-increased miR-34c could interfere IL-6-triggered CRC progression. © 2015 Yang et al.


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.


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.


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.

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