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Articles by J Zheng
Total Records ( 7 ) for J Zheng
  X Yan , S Walayat , Q Shi , J Zheng and Y. Wang
 

Though accumulated evidence has demonstrated the transformation capacity of human papillomavirus (HPV) type 18 protein E7, the underlying mechanism is still arguable. Developing a protein transduction domain (PTD)-linked E7 molecule is a suitable strategy for assessing the biological functions of the protein. In the present study, HPV18 E7 protein fused to an N-terminal PTD was expressed in the form of glutathione S-transferase fusion protein in Escherichia coli with pGEX-4T-3 vector. After glutathione-Sepharose 4B bead affinity purification, immunoblot identification and thrombin cleavage, the PTD-18E7 protein showed structural and functional activity in that it potently transduced the cells and localized into their nuclei. The PTD-18E7 protein transduced the NIH3T3 cells in 30 min and remained stable for at least 24 h. In addition, the PTD-18E7 protein interacted with retinoblastoma protein (pRB) and caused pRB degradation in the transduced NIH3T3 cells. In contrast to the pRB level, p27 protein level was elevated in the transduced NIH3T3 cells. The PTD-18E7 protein gives us a new tool to study the biological functions of the HPV E7 protein.

  J Zheng , W Jing and R. J. Orentas
 

Neuroblastoma is one of the most common solid tumors in infancy and early childhood. Using the A/J mouse and a syngeneic neuroblastoma cell line AGN2a, we induced a strong anti-neuroblastoma cellular immune response when AGN2a transfected to express costimulatory molecules (CD80/CD86/CD54/CD137L) was used as a vaccine in the context of regulatory T cell blockade. Strong humoral immunity was induced by AGN2a-4p immunization in the context with regulatory T cell blockade. Serum from treated mice was used to screen an AGN2a cDNA expression library that was constructed with ZAP express vector in order to identify tumor-associated antigens by SEREX. Twenty-one clones were identified by sequencing and comparative analysis of gene pools. Most transcripts play some roles in the neuronal differentiation, cell metabolism, or have previously been identified as transcripts that are over-expressed in other malignancies. The most commonly identified tumor-associated antigen, using serum from AGN2a-4p immunization with Treg blockade mice, was YB-1 protein that also induced a T cell response. These results indicated that potential neuroblastoma-associated antigens were found by the sera from mice immunized with tumor cells expressing costimulatory molecules with regulatory T cell function blockade. The identification of YB-1 as tumor-associated antigens capable of eliciting a T cell response validates our experimental approach and argues for the antigens we have identified here to be evaluated as targets of effector immunity and as vaccine candidates.

  J Schwock , N Dhani , M. P. J Cao , J Zheng , R Clarkson , N Radulovich , R Navab , L. C Horn and D. W. Hedley
 

Focal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase and key modulator of integrin signaling, is widely expressed in different tissues and cell types. Recent evidence indicates a central function of FAK in neoplasia where the kinase contributes to cell proliferation, resistance to apoptosis and anoikis, invasiveness, and metastasis. FAK, like other signaling kinases, is dependent on the chaperone heat shock protein 90 (Hsp90) for its stability and proper function. Thus, inhibition of Hsp90 might be a way of disrupting FAK signaling and, consequently, tumor progression. FAK is expressed in high-grade squamous intraepithelial lesions and metastatic cervical carcinomas but not in nonneoplastic cervical mucosa. In SiHa, a cervical cancer cell line with characteristics of epithelial-to-mesenchymal transition, the stable expression of dominant-negative FAK-related nonkinase decreases anchorage independence and delays xenograft growth. FAK-related nonkinase as well as the Hsp90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin both negatively interfere with FAK signaling and focal adhesion turnover. Short-term 17-dimethylaminoethylamino-17-demethoxygeldanamycin treatment prolongs survival in a SiHa lung metastasis model and chronic administration suppresses tumor growth as well as metastatic spread in orthotopic xenografts. Taken together, our data suggest that FAK is of importance for tumor progression in cervical cancer and that disruption of FAK signaling by Hsp90 inhibition might be an avenue to restrain tumor growth as well as metastatic spread. [Cancer Res 2009;69(11):4750–9]

  L Wang , J Zheng , Y Du , Y Huang , J Li , B Liu , C. j Liu , Y Zhu , Y Gao , Q Xu , W Kong and X. Wang
 

Rational: Vascular smooth muscle cells (VSMCs) switching from a contractile/differentiated to a synthetic/dedifferentiated phenotype has an essential role in atherosclerosis, postangioplastic restenosis and hypertension. However, how normal VSMCs maintain the differentiated state is less understood.

Objective: We aimed to indentify the effect of cartilage oligomeric matrix protein (COMP), a normal vascular extracellular matrix, on modulation of VSMCs phenotype.

Methods and Results: We demonstrated that COMP was associated positively with the expression of VSMC differentiation marker genes during phenotype transition. Knockdown of COMP by small interfering (si)RNA favored dedifferentiation. Conversely, adenoviral overexpression of COMP markedly suppressed platelet-derived growth factor-BB-elicited VSMC dedifferentiation, characterized by altered VSMC morphology, actin fiber organization, focal adhesion assembly, and the expression of phenotype-dependent markers. Whereas 7 integrin coimmunoprecipitated with COMP in normal rat VSMCs and vessels, neutralizing antibody or siRNA against 7 integrin inhibited VSMC adhesion to COMP, which indicated that 7β1 integrin is a potential receptor for COMP. As well, blocking or interference by siRNA of 7 integrin completely abolished the effect of COMP on conserving the contractile phenotype. In accordance, ectopic adenoviral overexpression of COMP greatly retarded VSMC phenotype switching, rescued contractility of carotid artery ring, and inhibited neointima formation in balloon-injured rats.

Conclusions: Our data suggest that COMP is essential for maintaining a VSMC contractile phenotype and the protective effects of COMP are mainly mediated through interaction with 7β1 integrin. Investigations to identify the factors affecting the expression and integrity of COMP may provide a novel therapeutic target for vascular disorders.

  J Zheng , G Wang , G. Y Yang , D Wang , X Luo , C Chen , Z Zhang , Q Li , W Xu , Z Li and D. Wang
  Objective

This Phase II study was conducted to evaluate the activity and feasibility of a regimen of nedaplatin and 5-fluorouracil as induction chemotherapy, followed by intensity-modulated radiotherapy concurrent with chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

Methods

Patients received neoadjuvant chemotherapy comprised two cycles of 5-fluorouracil at 700 mg/m2/day administered on days 1–4 as continuous intravenous infusion and nedaplatin (100 mg/m2 administered i.v. over 2 h) given after the administration of 5-fluorouracil on day 1, repeated every 3 weeks, followed by intensity-modulated radiotherapy concurrent with nedaplatin. During intensity-modulated radiotherapy, nedaplatin was administered at a dose of 100 mg/m2 intravenous infusion on days 1, 22 and 43, given ~60 min before radiation.

Results

Fifty-nine (95.8%) of the 60 patients were assessable for response. Thirty-eight cases of complete response and 14 cases of partial response were confirmed after completion of chemoradiation, with the objective response rate of 86.7% (95% CI, 78.1–95.3%). The median follow-up period was 48 months (range, 30–62 months). The 3-year progression-free survival and overall survival were 75.0% (95% CI, 63.0–87.0%) and 85.5% (95% CI, 75.9–95.1%). No patient showed Grade 3 or higher renal dysfunction. The most commonly observed late effect was xerostomia, but the severity diminished over time, and the detectable xerostomia at 24 months was 10.2%. There were no treatment-related deaths during this study.

Conclusions

Neoadjuvant chemotherapy with nedaplatin and 5-fluorouracil followed by concomitant nedaplatin and intensity-modulated radiotherapy is an effective and safe treatment for Southern China patients affected by locoregionally advanced nasopharyngeal carcinoma.

  W. x Liao , L Feng , H Zhang , J Zheng , T. R Moore and D. b. Chen
 

On vascular endothelial growth factor (VEGF) stimulation, both VEGF R1 and R2 receptors were phosphorylated in ovine fetoplacental artery endothelial (oFPAE) cells. Treatment with VEGF stimulated both time- and dose-dependent activation of ERK2/1 in oFPAE cells. VEGF-induced ERK2/1 activation was mediated by VEGFR2, but not VEGFR1, and was linked to intracellular calcium, protein kinase C, and Raf-1. VEGF stimulated oFPAE cell proliferation, migration, and tube formation in vitro. Blockade of ERK2/1 pathway attenuated VEGF-induced cell proliferation and tube formation but failed to inhibit migration in oFPAE cells. Disruption of caveolae by cholesterol depletion with methyl-β-cyclodextrin or by down-regulation of its structural protein caveolin-1 blunted VEGF-induced ERK2/1 activation, proliferation, and tube formation in oFPAE cells, indicating an essential role of integral caveolae in these VEGF-induced responses. Adenoviral overexpression of caveolin-1 and addition of a caveolin scaffolding domain peptide also inhibited VEGF-stimulated ERK2/1 activation, cell proliferation, and tube formation in oFPAE cells. Furthermore, molecules comprising the ERK2/1 signaling module, including VEGFR2, protein kinase C, Raf-1, MAPK kinase 1/2, and ERK2/1, resided with caveolin-1 in caveolae. VEGF transiently stimulated ERK2/1 activation in the caveolae similarly as in intact cells. Caveolae disruption greatly diminished ERK2/1 activation by VEGF in oFPAE cell caveolae. We conclude that caveolae function as a platform for compartmentalizing the VEGF-induced ERK2/1 signaling module. Caveolin-1 and caveolae play a paradoxical role in regulating VEGF-induced ERK2/1 activation and in vitro angiogenesis as evidenced by the similar inhibitory effects of down-regulation and overexpression of caveolin-1 and disruption of caveolae in oFPAE cells.

 
 
 
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