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Snail promotes metastasis of nasopharyngeal carcinoma partly by down-regulating TEL2

Cancer Communications 2018年第1期38卷 622-631页

作者： yi Sang Chun Cheng yi-xin zeng Tiebang Kang State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterNo.651 Dongfeng East RoadGuangzhou 510060People’s Republic of China Department of Center Laboratory The Eighth Affiliated Hospital of Sun Yat-Sen UniversityNo.3025 Shennan Middle RoadShenzhen 518033People’s Republic of China Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment The Third Affiliated Hospital of Nanchang UniversityNo.128 Xianshan North RoadNanchang 330008People’s Republic of China

Background:Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma(NPC).We previously reported that TEL2,a negative regulator of SERPINE1,could inhibit NPC metastasis to lymph nodes.Method:A series of in vivo and in vitro assays were performed to elucidate the regulation between Snail and TEL2.TEL2 expression was analyzed in three representative NPC cell lines expressing low levels of Snail(S26,6-10B,HK1)and two cell lines expressing high levels of Snail(S18,5-8F).Luciferase and chromatin immunoprecipitation assays were used to analyze the interaction between Snail and TEL2.The roles of the Snail/TEL2 pathway in cell migration and invasion of NPC cells were examined using transwell assays.Metastasis to the lungs was examined using nude mouse receiving NPC cells injection through the tail vein.Results:Ectopic Snail expression down-regulated TEL2 at the mRNA and protein levels,whereas knockdown of Snail using short hairpin RNA up-regulated TEL2.Luciferase and chromatin immunoprecipitation assays indicated that Snail binds directly to the TEL2 promoter.Ectopic Snail expression enhanced migration and invasion of NPC cells,and such effects were mitigated by TEL2 overexpression.TEL2 overexpression also attenuated hypoxia-induced cell migration and invasion,and increased the number of metastatic pulmonary nodules.Snail overexpression reduced the number of metastatic pulmonary nodules.Conclusions:TEL2 is a novel target of Snail and suppresses Snail-induced migration,invasion and metastasis in NPC.

关键词： TEL2 Snail Metastasis Nasopharyngeal carcinoma

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Centrifugation: an important pre-analytic procedure that influences plasma microRNA quantification during blood processing

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Chinese Journal of Cancer 2013年第12期32卷 667-672页

作者： Xiao-Hui Zheng Cui Cui xin-Xi Zhou yi-xin zeng Wei-Hua Jia State Key Laboratory of Oncology in South China Bank of Tumor Resource Sun Yat-sen University Cancer Center

Circulating microRNAs are robustly present in plasma or serum and have become a research focus as biomarkers for tumor diagnosis and prognosis.Centrifugation is a necessary procedure for obtaining highquality blood supernatant.Herein,we investigated one-step and two-step centrifugations,two centrifugal methods routinely used in microRNA study,to explore their effects on plasma microRNA quantification.The microRNAs obtained from one-step and two-step centrifugations were quantified by microarray and TaqMan-based real-time quantitative polymerase chain reaction(Q-PCR).Dynamic light scattering was performed to explore the difference underlying the two centrifugal methods.The results from the microarray containing 1,347 microRNAs showed that the signal detection rate was greatly decreased in the plasma sample prepared by two-step centrifugation.More importantly,the microRNAs missing in this plasma sample could be recovered and detected in the precipitate generated from the second centrifugation.Consistent with the results from microarray,a marked decrease of three representative microRNAs in twostep centrifugal plasma was validated by Q-PCR.According to the size distribution of all nanoparticles in plasma,there were fewer nanoparticles with size>1,000 nm in two-step centrifugal plasma.Our experiments directly demonstrated that different centrifugation methods produced distinct quantities of plasma microRNAs.Thus,exosomes or protein complexes containing microRNAs may be involved in large nanoparticle formation and may be precipitated after two-step centrifugation.Our results remind us that sample processing methods should be first considered in conducting research.

关键词： microRNA 离心分离血浆定量分析血液预分析小分子RNA 微小RNA

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Air pollution:a smoking gun for cancer

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Chinese Journal of Cancer 2014年第4期33卷 173-175页

作者： Wei Zhang Chao-Nan Qian yi-xin zeng Department of Pathology The University of Texas MD Anderson Cancer Center State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine Sun Yat-sen University Cancer Center Peking Union Medical College

Once considered a taboo topic or stigma,cancer is the number one public health enemy in the world.Once a product of an almost untouchable industry,tobacco is indisputably recognized as a major cause of cancer and a target for anticancer efforts.With the emergence of new economic powers in the world,especially in highly populated countries such as China,air pollution has rapidly emerged as a smoking gun for cancer and has become a hot topic for public health debate because of the complex political,economic,scientific,and technologic issues surrounding the air pollution problem.This editorial and the referred articles published in this special issue of the Chinese Journal of Cancer discuss these fundamental questions.Does air pollution cause a wide spectrum of cancers?Should air pollution be considered a necessary evil accompanying economic transformation in developing countries?Is an explosion of cancer incidence coming to China and how soon will it arrive?What must be done to prevent this possible human catastrophe?Finally,the approaches for air pollution control are also discussed.

关键词：空气污染控制癌症证据发展中国家经济转型公共健康人口密集公共卫生

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GWAS signals across the HLA regions:revealing a clue for common etiology underlying infectious tumors and other immunity diseases

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Chinese Journal of Cancer 2011年第4期30卷 226-230页

作者： yin Yao Shugar ying Wang Wei-Hua Jia yi-xin zeng Unit of Statistical Genomics Intramural Research Program National Institute of Mental Health National Institute of Health Bethesda Maryland 20892 USA Department of Psychiatry and Behavioral Sciences the Johns Hopkins University School of Medicine Baltimore Maryland 21287 USA State Key Laboratory ot Oncology in South China Guangzhou Guangdong 510060 P. R. China Department of Experimental Research Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 P. R. China.

Increasing evidence suggests that multiple genes in the human leukocyte antigen(HLA) regions play an important role in development of cancers and immunity disorders.However,the biological mechanisms of the HLA associations are not well understood.We recently conducted a survey of all genome-wide association studies(GWAS) with significant findings in the HLA regions and concluded that diseases such as cancer and immune disorders are more likely to be associated with genetic variants located in the HLA regions than other diseases.This finding is suggestive for testing a hypothesis of a common etiology of infectious tumors and other immunity diseases.

关键词：免疫系统 HLA 传染性疾病病因肿瘤人类白细胞抗原信号

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Repressing malic enzyme 1 redirects glucose metabolism,unbalances the redox state,and attenuates migratory and invasive abilities in nasopharyngeal carcinoma cell lines

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Chinese Journal of Cancer 2012年第11期31卷 519-531页

作者： Fang-Jing Zheng Hao-Bin Ye Man-Si Wu yi-Fan Lian Chao-Nan Qian yi-xin zeng State Key Lab Oncol South China Guangzhou 510060GuangdongPeoples R China Sun Yat Sen Univ Dept Expt ResCtr CancGuangzhou 510060GuangdongPeoples R China Sun Yat Sen Univ Dept Nasopharyngeal CarcinomaCtr CancGuangzhou 510060GuangdongPeoples R China Univ Rochester Med CtrDept PatholRochesterNY 14642 USA

A large amount of nicotinamide adenine dinucleotide phosphate(NADPH) is required for fatty acid synthesis and maintenance of the redox state in cancer cells.Malic enzyme 1(ME1)-dependent NADPH production is one of the three pathways that contribute to the formation of the cytosolic NADPH pool.ME1 is generally considered to be overexpressed in cancer cells to meet the high demand for increased de novo fatty acid synthesis.In the present study,we found that glucose induced higher ME1 activity and that repressing ME1 had a profound impact on glucose metabolism of nasopharyngeal carcinoma(NPC) cells.High incorporation of glucose and an enhancement of the pentose phosphate pathway were observed in ME1-repressed cells.However,there were no obvious changes in the other two pathways for glucose metabolism:glycolysis and oxidative phosphorylation.Interestingly,NADPH was decreased under low-glucose condition in ME1-repressed cells relative to wild-type cells,whereas no significant difference was observed under high-glucose condition.ME1-repressed cells had significantly decreased tolerance to low-glucose condition.Moreover,NADPH produced by ME1 was not only important for fatty acid synthesis but also essential for maintenance of the intracellular redox state and the protection of cells from oxidative stress.Furthermore,diminished migration and invasion were observed in ME1-repressed cells due to a reduced level of Snail protein.Collectively,these results suggest an essential role for ME1 in the production of cytosolic NADPH and maintenance of migratory and invasive abilities of NPC cells.

关键词：氧化还原状态鼻咽癌细胞苹果酸酶细胞株葡萄糖糖代谢还原型烟酰胺腺嘌呤二核苷酸侵袭

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High Expression of p300 in Human Breast Cancer Correlates with Tumor Recurrence and Predicts Adverse Prognosis

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Chinese Journal of Cancer Research 2011年第3期23卷 201-207页

作者： Xiang-sheng Xiao Mu-yan Cai Jie-wei Chen xin-yuan Guan Hsiang-fu Kung yi-xin zeng Dan Xie State Key Laboratory of Oncology in South China Guangzhou 510060China Department of Breast Oncology Guangzhou 510060China Department of Pathology Sun Yat-sen University Cancer CenterGuangzhou 510060China The Chinese University of Hong Kong Hong KongChina

Objective：Transcriptional coactivator p300 has been shown to play a variety of roles in the transcription process and mutation of p300 has been found in certain types of human cancers.However,the expression dynamics of p300 in breast cancer （BC） and its effect on BC patients＇ prognosis are poorly understood.Methods：In the present study,the methods of tissue microarray and immunohistochemistry （IHC） were used to investigate the protein expression of p300 in BCs.Receiver operating characteristic （ROC） curve analysis,Spearman＇s rank correlation,Kaplan-Meier plots and Cox proportional hazards regression model were utilized to analyze the data.Results：Based on the ROC curve analysis,the cutoff value for p300 high expression was defined when the H score for p300 was more than 105.High expression of p300 could be observed in 105/193 （54.4%） of BCs,in 6/25 （24.0%） of non-malignant breast tissues,respectively （P=0.004）.Further correlation analysis showed that high expression of p300 was positively correlated with higher histological grade,advanced clinical stage and tumor recurrence （P0.05）.In univariate survival analysis,a significant association between high expression of p300 and shortened patients＇ survival and poor progression-free survival was found （P0.05）.Importantly,p300 expression was evaluated as an independent prognostic factor in multivariate analysis （P0.05）.Conclusion：Our findings provide a basis for the concept that high expression of p300 in BC may be important in the acquisition of a recurrence phenotype,suggesting that p300 high expression,as examined by IHC,is an independent biomarker for poor prognosis of patients with BC.

关键词： Breast cancer p300 Tumor recurrence Prognosis

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Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes

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Signal Transduction and Targeted Therapy 2021年第3期6卷 909-924页

作者： Li Zhong Dan Liao Jingjing Li Wenqiang Liu Jingxuan Wang Cuiling zeng xin Wang Zhiliang Cao Ruhua Zhang Miao Li Kuntai Jiang yi-xin zeng Jianhua Sui Tiebang Kang State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouChina Department of Oncology The Fifth Affiliated Hospital of Sun Yat-Sen UniversityZhuhaiGuangdongChina National Institute of Biological Sciences BeijingChina Sun Yat-sen University School of Medicine ShenzhenChina Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhouChina

It remains unknown for decades how some of the therapeutic fusion proteins positive in a small percentage of cancer cells account for patient outcome.Here,we report that osteosarcoma Rab22a-NeoF1 fusion protein,together with its binding partner PYK2,is sorted into exosomes by HSP90 via its KFERQ-like motif(RVLFLN^(142)).The exosomal Rab22a-NeoF1 fusion protein facilitates the pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages.The exosomal PYK2 activates RhoA in its negative recipient osteosarcoma cells and induces signal transducer and activator of transcription 3 activation in its recipient macrophages to increase M2 phenotype.Consequently,lung metastases of its recipient osteosarcoma cells are promoted by this exosomal Rab22a-NeoF1 fusion protein,and this event can be targeted by disrupting its interaction with PYK2 using a designed internalizing RGD peptide.

关键词： osteosarcoma lung metastasis

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Translational medicine promising personalized therapy inoncology

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Frontiers of Medicine 2010年第4期4卷 351-355页

作者： yi-xin zeng Xiao-Shi ZHANG Qiang LIU State Key Laboratory of Oncology in South China Sun Yat-sen UniversityGuangzhou 510060China Experimental Research Department Sun Yat-sen UniversityGuangzhouGuangdong 510060China Cancer Biotherapy Center Sun Yat-sen UniversityGuangzhou 510060China

Translational medicine has newly emerged to bridge the gap between bench-related basic science research and bedside clinical practice.From early diagnosis to late-stage disease treatment,translational medicine has transformed the clinical practice by making personalized medicine possible.Attributing to the progress in translational medical research,cancer therapy has evolved from non-specific cytotoxic drugs against both tumor and normal proliferating cells to more specific small molecule chemical and immunotherapy approaches.Small molecular agents are directed at unique pathogenesis of cancer cells,whereas immunotherapeutic agents target the cancer immune response.Both approaches aim to produce less toxicity with high effectiveness.Therapeutic regimens with these agents in biomarker-classified sensitive populations promises a personalized approach in modern oncology.

关键词： clinical diagnosis drugs

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The Chinese Journal of Cancer is indexed in Science CitationIndex(SCI) Expanded

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Chinese Journal of Cancer 2014年第8期33卷 367-368页

作者： yi-xin zeng Wei Zhang Chao-Nan Qian Rui-Hua Xu Ji Ruan Peking Union Medical College Chinese Journal of Cancer Department of Pathology The University of Texas MD Anderson Cancer Center Houston State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine Sun Yat-sen University Cancer Center Department of Editorial Office Sun Yat-sen University Cancer Center Editorial Office

On July 22,2014,the Chinese Journal of Cancer(CJC)received a notification from Thomson Reuters that the publications of our journal starting from 2012 have been accepted for coverage in Science Citation Index Expanded,available at the Web of Science,Core Collection,Biological Abstracts,and Biosis Previews.What this means in practical terms is that CJC will receive its first official impact factor(IF)in 2015.This is an important milestone in the history

关键词：科学引文索引癌症中国 SCI BIOSIS 核心种质影响因子生物学

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Ex vivo expansion of tumor-infiltrating lymphocytes from nasopharyngeal carcinoma patients for adoptive immunotherapy

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Chinese Journal of Cancer 2012年第6期31卷 287-294页

作者： Jia He Xiao-Feng Tang Qiu-Yan Chen Hai-Qiang Mai Zhou-Feng Huang Jiang Li yi-xin zeng State Key Laboratory of Oncology in South China GuangzhouGuangdong 510060P.R.China Sun Yat-sen University Cancer Center GuangzhouGuangdong 510060P.R.China Departmentof Biotherapy Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China Department of Nasopharyngeal Carcinoma Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China

Establishing Epstein-Barr virus (EBV)-specific cytolytic T lymphocytes (EBV-CTLs) from peripheral blood mononuclear cells (PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). In the current study,we performed ex vivo expansion of tumor-infiltrating lymphocytes (TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody (OKT3), recombinant human interleukin (IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+T cells, a variable percentage of CD3+CD8+and CD3+CD4+T cells, and less than 10% of CD3-CD16+natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.

关键词：细胞毒性T淋巴细胞体外扩增免疫治疗恶性肿瘤鼻咽癌 Epstein-Barr病毒外周血单个核细胞浸润性

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