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Shou L.-M.,Soochow University of China | Zhang Q.-Y.,Soochow University of China | Li W.,Soochow University of China | Xie X.,Soochow University of China | And 11 more authors.
Oncology Reports | Year: 2013

Cancer metastasis is a highly coordinated and dynamic multistep process in which cancer cells interact with a variety of host cells. Morphological studies have documented the association of circulating tumor cells with host platelets, where a surface coating of platelets protects tumor cells from mechanical trauma and the immune system. Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. Cantharidin and norcantharidin are potent protein phosphatase 2A (PP2A) inhibitors that exhibit in vitro and in vivo antitumor activity against several types of cancer, including breast cancer. We investigated whether cantharidin and norcantharidin could repress the ability of MCF-7 breast cancer cells to adhere to platelets. Using MTT, clone formation, apoptosis, adhesion and wound-healing assays, we found that cantharidin and norcantharidin induced apoptosis and repressed MCF-7 cell growth, adhesion and migration. Moreover, we developed a flow cytometry-based analysis of tumor cell adhesion to platelets. We proved that cantharidin and norcantharidin repressed MCF-7 cell adhesion to platelets through downregulation of α2 integrin, an adhesion molecule present on the surface of cancer cells. The repression of α2 integrin expression was found to be executed through the protein kinase C pathway, the activation of which could have been due to PP2A inhibition.


Mao Y.,Soochow University of China | Li W.,Soochow University of China | Chen K.,Soochow University of China | Xie Y.,Soochow University of China | And 7 more authors.
Oncotarget | Year: 2015

B7-H1 and B7-H3, two members of the B7 family that are thought to regulate T-cell activation, are expressed in human non-small cell lung cancer (NSCLC). However, their prognostic significance is poorly understood. In the present study we reported that B7-H1 and B7-H3 were expressed in 96/128 (72.7%) and 89/128 (69.5%) samples, respectively. B7-H1 and B7-H3 expression and the number of infiltrating T-cell intracellular antigen-1+ and interferon-γ + cells in NSCLC tissues were significantly higher than those in the adjacent tissues (p < 0.01). High B7-H1 or B7-H3 expression was associated with lymph node metastasis and TNM stage (p < 0.05, respectively). Sex, TNM stage, B7-H1, B7-H3, and T-cell intracellular antigen-1 expression remained significant prognostic factors after adjusting for other prognostic factors in a multivariate Cox proportional hazards regression model. In vitro studies revealed that knockdown of B7-H3 on tumor cells enhanced T-cell growth and interferon-γ secretion when stimulated by anti-CD3 and anti-CD28 monoclonal antibodies. Interferon-γ reduced CXCR4 expression on cancer cells and inhibited the CXCL12-induced cell migration.B7-H1 and B7-H3 are independent predictors of poorer survival in patients with NSCLC. Interference of the signal pathways of these negative regulatory molecules might be a new strategy for treating NSCLC.


Zhou H.,Soochow University of China | Zhou H.,Jiangnan University | Hu Y.,Jiangnan University | Wang W.,Soochow University of China | And 9 more authors.
Oncology Letters | Year: 2015

Octamer-binding transcription factor 4 (Oct-4), is an essential transcription factor, which is required for pluripotency and self-renewal in embryonic stem cells and germ cells. It is also involved in maintaining cancer stem-like properties in certain types of tumor, and is an important biomarker for cancer stem cells. The present study investigated whether Oct-4 expression was associated with colorectal cancer (CRC). In order to achieve this, primary CRC tissues, matched non-tumor tissues and benign polyp tissues, representing different stages of carcinogenesis, were obtained, and Oct-4 expression was analyzed using reverse transcription-quantitative polymerase chain reaction, flow cytometry analysis and immunohistochemistry. Furthermore, the medical records of patients with CRC were reviewed, and clinicopathological analysis was performed in order to assess the association between Oct-4 expression and certain clinicopathological parameters. It was shown that the transcription and translation of Oct-4 increased in a stepwise manner, from non-tumor to benign polyp tissues, and from benign polyps to CRC tissues. Oct-4 expression in CRC was significantly correlated with histological grade (P=0.007), lymph node metastasis (P=0.027), distant metastasis (P=0.017) and TNM stage (P=0.041). Kaplan-Meier survival curve analysis demonstrated that Oct-4+ cases had a shorter median survival time (37.0 months) compared with Oct-4- cases (76.0 months; P=0.001). These results indicated that aberrant expression of Oct-4 may be involved in the development of CRC. Thus, Oct-4 may be a biomarker for the prediction, diagnosis or assessment of prognosis in CRC, in addition to a potential target for the treatment of this disease. © 2015, Spandidos Publications. All rights reserved.


Xia S.,Soochow University of China | Feng Z.,Soochow University of China | Qi X.,Jiangnan University | Yin Y.,Jiangnan University | And 6 more authors.
Medical Oncology | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) is one of the most leading causes of cancer-related death. Cancer stem cell is responsible for tumor initiation, metastasis and relapse. Sox9 is a pancreatic stem cell marker. PI3K/PTEN/Akt/mTORC is an important signal for maintaining stem cells. The purpose of this study is to determine the expression pattern of Sox9 and p-Akt in human PDAC and its correlation with prognosis. Immunohistochemical analysis was used to explore the expression of Sox9 and p-Akt in 88 human PDAC patients. The Pearson’s test was used to compare the clinicopathological parameters between negative and positive expressors. The Pearson’s correlation analysis was used to explore the relationship between Sox9 and p-Akt expression. Kaplan–Meier’s method and Cox regression analysis were used to analyze patients’ survival. The results showed that Sox9 and p-Akt overactivated in PDAC (p = 0.011, p = 0.008). Sox9-positive expression is significantly associated with distant metastasis (p = 0.046). p-Akt-positive expression is significantly associated with distant metastasis (p = 0.000), TNM stage (0.001) and PCNA expression (p = 0.000). Sox9 expression is positively correlated with p-Akt expression (r = 0.314, p = 0.003). In 54 patients with survival information, both Sox9- and p-Akt-positive expressions are associated with unfavorable prognosis (p = 0.002, p = 0.000). Sox9 and p-Akt double-positive expressor showed much poorer prognosis (p = 0.000). Cox regression analysis showed that Sox9- or p-Akt-positive expression and LN metastasis were independent prognostic factors. This study provides the first evidence that Sox9 and p-Akt are both relevant to distant metastasis and proliferation. Our data suggest the potential of Sox9 and p-Akt as prognostic biomarkers for PDAC. © 2014, Springer Science+Business Media New York.


Chen Q.,Soochow University of China | Xia X.,Soochow University of China | Xia X.,Nantong Tumor Hospital | Wu S.,Soochow University of China | And 12 more authors.
Cell Biochemistry and Function | Year: 2014

Enterocytes die during high-dose radiation exposure in radiation accidents. The modality of cell death has a profound effect on the therapeutic response. The ilea from mice with 15Gy total body irradiation (TBI) were drawn, morphological features observed by hematoxylin and eosin staining and transmission electron micrographs. The biochemical features of mouse ileum presented with the structure were cleaved Caspase-3 (apoptosis marker), Light Chain 3 (LC3)-I's conversion to LC3-II (autophagy marker) and high mobility group box chromosomal protein 1's secretion (necrosis marker). Then, the autophagy inhibitor (3-methyladenine), caspase inhibitor (Z-VAD-FMK) or necrosis inhibitor (necrostatin) was used to prevent death. Apoptosis, autophagy and necrosis were all appeared in the ileum, but necrosis had the biggest size; the use of 3-methyladenine and Z-VAD-FMK prolong one day's life of the mice after 15Gy TBI, necrostatin significantly extended the lifespan of 15Gy irradiated mice (p<0.05). The results suggest that the death of enterocytes could not be classified into one type of cell death but rather as 'mixed death.' © 2014 John Wiley & Sons, Ltd.


Chen K.,Soochow University of China | Shou L.-M.,Soochow University of China | Lin F.,Soochow University of China | Duan W.-M.,Soochow University of China | And 6 more authors.
Anti-Cancer Drugs | Year: 2014

We found that artesunate (ART) inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells. ART arrested the cell cycle in the G2/M phase, which was accompanied by an upregulation of p21. ART upregulated the expression of Beclin1, an initiator of autophagy (type II programmed cell death). In addition, ART stimulated the aggregation of LC3, which is considered to be a marker of autophagosome formation. We further verified the transformation of LC3 from type I into type II. 3-MA, a classical autophagy inhibitor, attenuated ART-induced autophagosome formation, cell growth repression, G2/M arrest, and p21 upregulation. Autophagy induction and p21 upregulation were also repressed by knockdown of Beclin1. Furthermore, ART sensitized breast cancer cells to the chemotherapeutic agent epirubicin through an autophagy-dependent cascade. Our study showed that ART induced autophagy in breast cancer cells and indicated that the anticancer effects of ART were exerted through an autophagy pathway. Moreover, ART sensitized breast cancer cells to epirubicin chemotherapy. Our results provide a basis for further development of ART as a novel therapeutic agent for the treatment of breast cancer. © 2014 Wolters Kluwer Health Lippincott Williams & Wilkins.


Shen M.,Soochow University of China | Duan W.-M.,Soochow University of China | Wu M.-Y.,Soochow University of China | Wang W.-J.,Soochow University of China | And 12 more authors.
Oncology Reports | Year: 2015

Breast cancer is one of the most common cancers affecting women worldwide. Conventional chemotherapy is still one of the major approaches to the treatment of breast cancer. Autophagy, also termed as type II programmed cell death (PCD), exhibits either a protumorigenic or antitumorigenic function. In the present study, we investigated whether autophagy could be involved in the effect of chemotherapy against breast cancer. Epirubicin, docetaxel, methotrexate, cyclophosphamide, fluorouracil (5-FU) and cisplatin were applied in the present investigation. All of these chemotherapeutics presented cytotoxicity against breast cancer cells. DsRed-LC3 reporter assay revealed that only docetaxel and cisplatin induced autophagy. Autophagy inhibitor 3-methyladenine (3-MA) strengthened the cytotoxicity of docetaxel, yet impaired the cytotoxicity of cisplatin, suggesting that docetaxel stimulates protumorigenic autophagy, while cisplatin-induced autophagy could be antitumorigenic. Real-time PCR revealed that cisplatin upregulated multiple autophagy-related genes, including AMBRA1, ATG3, ATG4C, ATG4D, ATG5, ATG7, ATG13, ATG14, ATG16L2, Beclin1, DRAM1, GABARAP, GABARAPL1, GABARAPL2, HDAC6, IRGM, MAP1LC3B and ULK1, indicating that cisplatin induced autophagy through a multiple mechanism involved manner. © 2015, Spandidos Publications. All rights reserved.


Wang W.-J.,Soochow University of China | Wu M.-Y.,Soochow University of China | Shen M.,Soochow University of China | Zhi Q.,Soochow University of China | And 7 more authors.
International Journal of Oncology | Year: 2015

Increasing evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth, and are hypothesized to account for therapeutic resistance. Based on the expression of the surface markers CD44, CD24, and EPCAM, putative CSCs have also been identified in pancreatic cancers. It has been well established that aberrant activation of β-catenin signaling pathway may contribute to the maintenance of CSCs. Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. In our previous studies, we demonstrated that cantharidin treatment induced phosphorylation of β-catenin, leading to repression on β-catenin pathway. Therefore, in the present study, we investigated whether cantharidin and its derivant, norcantharidin, could repress the stemness of pancreatic cancer cells through repression on β-catenin pathway. By using microarray and flow cytometry, we found that treatment with cantharidin and norcantharidin repressed the expression of CD44, CD24, and EPCAM at both mRNA and protein levels, leading to decreased CD44+/CD24+/EPCAM+ proportion, the putative pancreatic CSC subset. Pretreatment with the β-catenin pathway inhibitor FH535, attenuated the cantharidin- and norcantharidin-inducrd repression on CD44, CD24, and EPCAM, suggesting cantharidin and its derivant repressed stemness of pancreatic cancer cells in β-catenin pathway-dependent manner. Furthermore, cantharidin and norcantharidin strengthened the cytotoxicity of gemcitabine and erlotinib, two well established pharmacotherapeutics against pancreatic cancers, indicating cantharidin and norcantharidin could be promising candidates for reversing drug resistance in pancreatic cancers. In conclusion, we presently propose that cantharidin and norcantharidin hold their promise in pancreatic cancer therapy through repression on stemness and strengthening the cytotoxicity of the present therapeutics.


Xu H.,Soochow University of China | Chen K.,Soochow University of China | Jia X.,University of Houston | Tian Y.,Suzhou Xiangcheng Peoples Hospital | And 8 more authors.
Oncologist | Year: 2015

Background. Diabetic patients with breast cancer receiving metformin and neo adjuvant chemotherapy have a higher pathologic complete response rate than do diabetic patients not receiving met for min, but findings on salvage treatment have been inconsistent. We performed a meta-analysis to assess the effect of adding met for min to standard therapy on the prognosis of breast cancer patients with diabetes. Methods. We searched Pub Med, Em base, Web of Science (Thomson Scientific), China Knowledge Resource Integrated Database, VIP journal integration platform, and Chinese BioMedical Literature Database from inception to January 10, 2015, without language restrictions, including references related to met for min, breast cancer, and prognosis. We performed the meta-analysis using a random-effects model, with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures. Results. A total of 11 studies consisting of 5,464 breast cancer patients with diabetes were included, comprising2, 760 patients who had received met for min and 2,704 patients who had not. The meta-analysis showed that met for min was associated with better overall survival times (HR: 0.53; 95% CI: 0.39-0.71) and cancer-specific survival times (HR: 0.89; 95% CI: 0.79-1.00). Subgroup analysis revealed that met for min improved the overall survival by 65% after adjusting for hormone receptor expression (HR: 0.35; 95% CI: 0.15-0.84). Taking met for min after the diagnosis of breast cancer was still associated with prolonged overall survival. Conclusion. The use of metformin in standard cancer therapy might improve both overall and cancer-specific survivals of diabetic patients with breast cancer © AlphaMed Press 2015.

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