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Cui J.,Xi'an Jiaotong University | Cui J.,Yan'an University | Guo Y.-H.,Shaanxi Province Cancer Hospital | Zhang H.-Y.,Yan'an University | And 7 more authors.
OncoTargets and Therapy | Year: 2014

Purpose: Celecoxib, an inhibitor of cyclooxygenase-2 (COX2), was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs), as well as elucidate the underlying mechanisms. Methods: The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. Results: MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 μmol/L) plus 5-fluorouracil (8.1 × 10-3 g/L) or sorafenib (4.4 μmol/L) increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR) and phosphorylated (p)-AKT expression. Gefitinib (5 μmol/L), which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 μmol/L) plus celecoxib (21.8 μmol/L) increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. Conclusion: Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2 MCSs. Our results provided molecular evidence to support celecoxib combination-treatment strategies for patients with human hepatocellular carcinoma. MCSs provided a good model to evaluate the interaction of anticancer drugs. © 2014 Cui et al.


Wang S.-H.,Xi'an Jiaotong University | Lu Q.-Y.,Liaocheng Peoples Hospital | Guo Y.-H.,Shaanxi Province Cancer Hospital | Song Y.-Y.,Xian Hospital of Traditional Chinese Medicine | And 2 more authors.
European Journal of Cancer | Year: 2016

Myeloid-derived suppressor cells (MDSCs) mostly consisting of polymorphonuclear (PMN)-MDSCs and mononuclear MDSCs have been considered to play critical roles in immunosuppression, angiogenesis, invasion and metastases of various tumours. However, it is still unclear the regulated mechanisms underlying the generation and immunosuppression of two major MDSC subsets. Here, we report Notch signalling was inhibited significantly in tumour-bearing mouse MDSCs, in which PMN-MDSCs were the major population. MDSCs without recombination signal binding protein-Jк (RBP-J), the critical transcription factor mediating signalling from all four mammalian Notch receptors, reduced their ability of inhibiting the proliferation and activation of allogenic T cells. RBP-J-deficient MDSCs could not down-regulate the expression of co-stimulation molecules on dendritic cells (DCs). The antigen presentation capacity of DCs co-cultured with RBP-J-deficient MDSCs was not impaired in contrast to controls. Moreover, we show the blockage of Notch signalling could improve the generation of PMN-MDSCs but inhibit the production of mononuclear MDSCs both in vitro and in vivo. Stat3 pathway was suppressed in MDSCs blocked Notch signalling and Stat3 activation by IL-6 could reverse the phenotype and immunosuppression of Notch signalling–deficient MDSCs. Therefore, targeting Notch signalling may be an effective therapeutic strategy in tumour therapy. © 2016 Elsevier Ltd


PubMed | Liaocheng Peoples Hospital, Xian Hospital of Traditional Chinese Medicine, Xi'an Jiaotong University and Shaanxi Province Cancer Hospital
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

Myeloid-derived suppressor cells (MDSCs) mostly consisting of polymorphonuclear (PMN)-MDSCs and mononuclear MDSCs have been considered to play critical roles in immunosuppression, angiogenesis, invasion and metastases of various tumours. However, it is still unclear the regulated mechanisms underlying the generation and immunosuppression of two major MDSC subsets. Here, we report Notch signalling was inhibited significantly in tumour-bearing mouse MDSCs, in which PMN-MDSCs were the major population. MDSCs without recombination signal binding protein-J (RBP-J), the critical transcription factor mediating signalling from all four mammalian Notch receptors, reduced their ability of inhibiting the proliferation and activation of allogenic T cells. RBP-J-deficient MDSCs could not down-regulate the expression of co-stimulation molecules on dendritic cells (DCs). The antigen presentation capacity of DCs co-cultured with RBP-J-deficient MDSCs was not impaired in contrast to controls. Moreover, we show the blockage of Notch signalling could improve the generation of PMN-MDSCsbut inhibit the production of mononuclear MDSCs both invitro and invivo. Stat3 pathway was suppressed in MDSCs blocked Notch signalling andStat3 activation by IL-6 could reverse the phenotype and immunosuppression of Notch signalling-deficient MDSCs. Therefore, targeting Notch signalling may be an effective therapeutic strategy in tumour therapy.


Lu J.,Shaanxi Province Cancer Hospital | Lu J.,PLA Fourth Military Medical University | Zhang F.,PLA Fourth Military Medical University | Yuan Y.,Shaanxi Province Cancer Hospital | And 3 more authors.
Oncology Reports | Year: 2013

All-trans retinoic acid (ATRA) is a potent chemo-preventive and therapeutic agent and exerts its effects by inducing growth arrest. In the present study, we demonstrated that ATRA activated the expression of p53 via Axin and induced cell cycle arrest at the G1/S phase and apoptosis of glioma cells. Briefly, C6 cells were treated with ATRA, and the levels of p53 mRNA and protein were determined by RT-PCR, western blotting and immunohistochemistry. The results showed that ATRA activated the expression of p53. In addition, ectopic expression of Axin by transient transfection of C6 cells with rAxin revealed that overexpression of Axin induced cell cycle arrest and apoptosis with an upregulation of p53. Furthermore, loss-of-function of Axin in glioma cells by RNAi blocked ATRA-induced cell cycle phase arrest and apoptosis via downregulation of p53. The present study revealed a novel function of Axin and identified it as an important regulator of ATRA-activated p53 expression.


Zhao S.-H.,PLA Fourth Military Medical University | Wang Y.,PLA Fourth Military Medical University | Wen L.,PLA Fourth Military Medical University | Zhai Z.-B.,Shaanxi province cancer hospital | And 7 more authors.
Journal of Translational Medicine | Year: 2013

Background: Basigin, which has four isoforms, has been demonstrated to be involved in progression of various human cancers. The aim of this study was to examine the prognostic value of basigin-2 protein expression in epithelial ovarian cancer. Furthermore, the function of basigin-2 in ovarian cancer was further investigated in cell culture models.Methods: Immunohistochemistry staining was performed to investigate basigin-2 expression in a total of 146 ovarian tissue specimens. Kaplan Meier analysis and Cox proportional hazards model were applied to assess the relationship between basigin-2 and progression-free survival (PFS) and overall survival (OS). Real-time PCR, RT-PCR and western blot were used to explore basigin-2, basigin-3 and basigin-4 expression in ovarian cancer cell lines and tissues. To evaluate possible contributions of basigin-2 to MMP secretion and cell migration and invasion, the overexpression vectors pcDNA3.1-basigin-2 and basigin-2 siRNA were transfected into HO-8910 and HO-8910 PM cells respectively.Results: High basigin-2 expression was associated with lymph-vascular space involvement, lymph node metastasis and poor prognosis of epithelial ovarian cancer. Multivariate analyses indicated that basigin-2 positivity was an independent prognostic factor for PFS (P = 0.006) and OS (P = 0.019), respectively. Overexpression of basigin-2 increased the secretion of MMP-2/9 and cancer cell migration and invasion of HO-8910 cells, whereas knockdown of basigin-2 reduced active MMP-2/9 production, migration and invasion of HO-8910 PM cells.Conclusions: The expression of basigin-2 might be an independent prognostic marker and basigin-2 inhibition would be a potential strategy for epithelial ovarian cancer patients, especially in inhibiting and preventing cancer cell invasion and metastasis. © 2013 Zhao et al.; licensee BioMed Central Ltd.


Cui J.,The First Affiliated Hospital Of Xian Jiaotong University | Cui J.,Yan'an University | Hu Y.-F.,Yan'an University | Feng X.-M.,Yan'an University | And 6 more authors.
Tumor Biology | Year: 2014

Epidermal growth factor receptor (EGFR) inhibitor treatment is a strategy for cancer therapy. However, innate and acquired resistance is a major obstacle of the efficacy. Autophagy is a self-digesting process in cells, which is considered to be associated with anti-cancer drug resistance. The activation of EGFR can regulate autophagy through multiple signal pathways. EGFR inhibitors can induce autophagy, but the specific function of the induction of autophagy by EGFR inhibitors remains biphasic. On the one hand, autophagy induced by EGFR inhibitors acts as a cytoprotective response in cancer cells, and autophagy inhibitors can enhance the cytotoxic effects of EGFR inhibitors. On the other hand, a high level of autophagy after treatment of EGFR inhibitors can also result in autophagic cell death lacking features of apoptosis, and the combination of EGFR inhibitors with an autophagy inducer might be beneficial. Thus, autophagy regulation represents a promising approach for improving the efficacy of EGFR inhibitors in the treatment of cancer patients. © 2014, International Society of Oncology and BioMarkers (ISOBM).

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