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缺氧诱导因子1α和血管内皮生长因子干扰性RNA抑制鼠视网膜新生血管的研究

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中华眼科杂志 2008年第10期44卷 921-928页

作者：蒋剑夏晓波许惠卓熊宇宋伟涛熊思齐李岩中南大学湘雅医院眼科长沙410008 美国texas大学md anderson癌症研究中心

目的探讨缺氧诱导因子1α（HIF-1α）和血管内皮生长因子（VEGF）小片段干扰性RNA（siRNA）对小鼠视网膜新生血管的抑制作用。方法本研究采用随机对照方法。构建HIF-1α siRNA重组质粒。C57BL／6J小鼠玻璃体腔注射增强型绿色荧光蛋白（E... 详细信息

目的探讨缺氧诱导因子1α（HIF-1α）和血管内皮生长因子（VEGF）小片段干扰性RNA（siRNA）对小鼠视网膜新生血管的抑制作用。方法本研究采用随机对照方法。构建HIF-1α siRNA重组质粒。C57BL／6J小鼠玻璃体腔注射增强型绿色荧光蛋白（EGFP）表达质粒pEGFP-N1，1d后视网膜铺片观察绿色荧光蛋白（GFP）的表达。选7天龄C57BL／6J小鼠90只，17只为正常组，73只建立氧诱导的视网膜新生血管模型，分为模型对照组、空载体组和基因治疗组（HIF1α siRNA组、VEGF siRNA组及共转染组）。于出氧舱前1d，向空载体组小鼠玻璃体腔注射空载体质粒；HIF—1α siRNA组注射HIF—1α siRNA，VEGF siRNA组注射VEGF165 siRNA，共转染组注射HIF1α siRNA＋VEGF165 siRNA。采用荧光造影视网膜铺片方法观察血管形态变化；制作组织切片计算突破视网膜内界膜的血管内皮细胞核数；采用逆转录聚合酶链反应和Western blot检测视网膜HIF—1α和VEGF的表达。采用单因素方差分析和组间最小显著差法进行统计学分析。结果pEGFP-N1经脂质体LF2000介导转染视网膜细胞后1d即可见GFP表达。基因治疗组较模型对照组新生血管丛明显减少，荧光渗漏明显减轻，其中共转染组效果最明显。基因治疗组[HIF-1α siRNA组为（27．73±2．33）个，VEGF siRNA组为（15．43±3．23）个，共转染组为（8．70±2．88）个]较其他3组突破视网膜内界膜的细胞核数量减少，差异均具有统计学意义（F=3016．527，P〈0．01）。视网膜HIF-1α mRNA及蛋白表达水平：模型对照组（1．08±0．06，0．383±0．009）和空载体组（1．09±0．05，0．386±0．010）较正常组（0．81±0．07，0．035±0．003）上调，而HIF-1α siRNA组（0．46±0．06，0．182±0．008）较模型对照组下调，抑制效率分别为57．4％和52．5％，差异均有统计学意义（F=139．804，2686．001；P〈0．01）。VEGF mRNA及蛋白表达水平：模型对照组（1．53±0．07，0．340±0．004）和空载体组（1．59±0．06，0．337±0．009）较正常组（0．27±0．08，0．051±0．008）明显上调，而基因治疗组较模型对照组明显下调，差异均有统计学意义（F=421．423，2513．583；P〈0．01），其中共转染组下调最明显，抑制效率分别为85．6％和80．9％。结论HIF-1α siRNA和VEGF165 siRNA均可有效抑制小鼠视网膜新生血管形成，两种siRNA共转染抑制效果最明显。

关键词：视网膜新生血管化 RNA,小分子干扰核蛋白质类 DNA结合蛋白质类血管内皮生长因子类基因疗法

Principles of microRNA involvement in human cancers

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Chinese Journal of Cancer 2011年第11期30卷 739-748页

作者： Hui Ling Wei Zhang George A. Calin Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston TX 77030 USA. Department of Pathology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA.

Naturally occurring microRNAs (miRNAs), small non-coding RNAs of 19 to 24 nucleotides (nt), are encoded in the genomes of invertebrates, vertebrates, and plants. miRNAs act as regulators of gene expression during development and differentiation at the transcriptional, posttranscriptional, and/or translational levels, although most target genes are still elusive. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In this review, we present principles related to the basic and translational research that has emerged in the last decade, a period that can be truly considered the "miRNA revolution" in molecular oncology. These principles include the regulation mechanism of miRNA expression, functions of miRNAs in cancers, diagnostic values and therapeutic potentials of miRNAs. Furthermore, we present a compendium of information about the main miRNAs that have been identified in the last several years as playing important roles in cancers. Also, we orient the reader to several additional reviews that may provide a deeper understanding of this new and exciting field of research.

关键词： microRNA 癌症 miRNA 非编码RNA 转录后水平无脊椎动物人类微RNA

Association between p21 Ser31Arg polymorphism and cancer risk:a meta-analysis

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Chinese Journal of Cancer 2011年第4期30卷 254-263页

作者： Hongxia Ma Ziyuan Zhou Sheng Wei Qingyi Wei Department of Epidemiology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA.

P21(CDKN1A),a key cell cycle regulatory protein that governs cell cycle progression from G1 to S phase,can regulate cell proliferation,growth arrest,and *** Ser31Arg polymorphism is located in the highly conserved region of p21 and may encode functionally distinct *** many epidemiological studies have been conducted to evaluate the association between the p21 Ser31Arg polymorphism and cancer risk,the findings remain *** meta-analysis with 33 077 cases and 45 013 controls from 44 published case-control studies showed that the variant homozygous 31Arg/Arg genotype was associated with an increased risk of numerous types of cancers in a random-effect model(homozygote comparison:OR = 1.17,95% CI = 0.99 to 1.37,P = 0.0002 for the heterogeneity test;recessive model comparison:OR = 1.16,95% CI = 1.01 to 1.33,P = 0.0001 for the heterogeneity test).Stratified analysis revealed that increased cancer risk associated with the 31Arg/Arg genotype remained significant in subgroups of colorectal cancer,estrogen-related cancer,Caucasians,population-based studies,studies with matching information or a larger sample *** analysis showed that tumor type contributed to substantial between-study heterogeneity(recessive model comparison:χ2 = 21.83,df = 7,P = 0.003).The results from this large-sample sized meta-analysis suggest that the p21 31Arg/Arg genotype may serve as a potential marker for increased cancer risk.

关键词： P21 多态性癌症风险随机效应模型协会细胞周期样本大小

Circulating levels of hydroxylated bradykinin function as an indicator of tissue HIF-1a expression

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Science Bulletin 2020年第18期65卷 1570-1579,M0004页

作者： Yang Liu Yajun Gu Serina Ng Zaian Deng Christopher J.Lyon Eugene J.Koay Bo Ning Matthew H.Katz Paul J.Chiao Jia Fan Haiyong Han Daniel Von Hoff Tony Y.Hu Department of Biochemistry and Molecular Biology Tulane University School of MedicineNew Orleans.LA 70112USA Department of Nanomedicine Houston Methodist Research InstituteHoustonTX 77030USA Molecular Medicine Division Translational Genomics Research InstitutePhoenixAZ 85004USA Department of Radiation Oncology Division of Radiation OncologyThe University of Texas M.D.Anderson Cancer CenterHoustonTX 77030USA Department of Surgical Oncology Division of SurgeryThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Molecular and Cellular Oncology Division of Basic SciencesThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.

关键词： HIF-1α Hypoxia Circulating indicator Hydroxyprolyl bradykinin P4HA1

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浙江大学学报（医学版） 2006年第1期35卷 45-49页

作者：陈斌何超劳伟峰黄学锋方炳良浙江大学医学院附属邵逸夫医院美国md anderson癌症中心

目的:探讨在端粒酶(hTERT)启动子驱动下TRA IL基因在大肠癌细胞HT-29的表达及其杀细胞作用。方法:通过腺病毒载体系统将hTERT启动子驱动的TNF相关凋亡诱导配体(TRA IL)基因转入大肠癌细胞HT-29,流式细胞仪检测GFP/TRA IL的表达和HT-29... 详细信息

目的:探讨在端粒酶(hTERT)启动子驱动下TRA IL基因在大肠癌细胞HT-29的表达及其杀细胞作用。方法:通过腺病毒载体系统将hTERT启动子驱动的TNF相关凋亡诱导配体(TRA IL)基因转入大肠癌细胞HT-29,流式细胞仪检测GFP/TRA IL的表达和HT-29细胞凋亡率。结果:端粒酶启动子驱动的GFP/TRA IL基因和CMV启动子驱动的GFP(绿色荧光蛋白)基因在HT-29内的表达率分别达31.4%和67.0%;GFP/TRA IL基因对HT-29细胞的生长抑制率和凋亡率分别达74.2%和25.8%,与PBS和A d/CMV-GFP比差异都有显著性意义(P<0.05)。结论:端粒酶启动子驱动的GFP/TRA IL融合基因能在大肠癌细胞中有效表达;TRA IL基因对大肠癌细胞HT-29有明显的抑制生长和促凋亡作用。

关键词：肿瘤坏死因子/分析端粒,末端转移酶/遗传学肿瘤细胞,培养的蛋白质类/化学结肠直肠肿瘤/病理学基因疗法细胞凋亡

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分子流行病学及其在转化医学中的作用

中华皮肤科杂志 2015年第3期48卷 147-150页

作者：吴息凤赵华 TX77030美国休斯敦德克萨斯大学MD安德森癌症中心流行病学系

进入21世纪以来，世界大多数发达国家医学研究策略发生了重大调整，更加强调将基础研究成果转化为临床应用，即转化医学。但是转化医学的发展并不顺利，至今为止，只有非常少量的基础研究成果被成功应用到了临床上。同时转化医学还面临... 详细信息

进入21世纪以来，世界大多数发达国家医学研究策略发生了重大调整，更加强调将基础研究成果转化为临床应用，即转化医学。但是转化医学的发展并不顺利，至今为止，只有非常少量的基础研究成果被成功应用到了临床上。同时转化医学还面临几个难题，例如，缺少具有多学科能力的转化医学研究人员，转化医学的周期过长等。显然，如何进一步促进转化医学的发展是一个难题。转化医学的研究是多层次，需要跨学科的团队合作，这个团队不仅需要分子生物学家、医学专家，还需要流行病学家。随着分子生物学的广泛应用和生物技术的飞速发展，流行病学已经从传统上的人群调查发展成了真正意义上的跨学科、跨领域的交叉学科，进入了基因和分子时代，即分子流行病学。

关键词：分子流行病学转化医学医学研究人员临床应用基础研究成果分子生物学发达国家成果转化

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滑膜肉瘤

中国组织化学与细胞化学杂志 2016年第2期25卷 174-178页

作者：谈东风 md anderson癌症中心病理与胃肠肿瘤科美国德克萨斯州休斯顿77030

滑膜肉瘤(Synovial sarcoma,SS)是最常见的肉瘤之一,可发生在身体的任何部位,尤其好发于20~30岁青年人。形态学上,双相型SS最常见,其次是少数单向型SS及低分化型SS。SS具有特异性的t(X;18)(p11;q11)染色体移位。临床症状与肿瘤发生部位... 详细信息

滑膜肉瘤(Synovial sarcoma,SS)是最常见的肉瘤之一,可发生在身体的任何部位,尤其好发于20~30岁青年人。形态学上,双相型SS最常见,其次是少数单向型SS及低分化型SS。SS具有特异性的t(X;18)(p11;q11)染色体移位。临床症状与肿瘤发生部位有关,一般表现为无痛性包块。诊断需要依据影像学资料。病理学检查包括特征性的SSX移位进行确诊。SS预后与患者年龄、肿瘤大小、分化程度、肿瘤部位、是否有转移有关。如果SS未发生转移,患者5年存活率较高。SS治疗需要临床多学科的共同参与。对于局限性的小肿块,外科手术是最有效的治疗方法。放疗,化疗或放化疗也在SS治疗中发挥作用,尤其是对于>5cm的较大肿块或SS发生转移的时候。特异性SSX融合基因和蛋白的靶向治疗等多种SS治疗方法尚在临床试验中。相信不久的将来对于滑膜肉瘤可能会开发出新的治疗策略。

关键词：滑膜肉瘤融合基因多学科染色体移位 t(X 18)(p11 q11)

A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses

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Cell Research 2007年第5期17卷 435-440页

作者： Seon Hee Chang Unit 906 houston USA TX 77030 7455 Fannin Department of Immunology md anderson Cancer Center

CD4+ helper T (TH) cells play crucial roles in immune responses. Recently a novel subset of TH cells, termed TH,TH17 or inflammatory TH (THi), has been identified as critical mediators of tissue inflammation. These cells produceIL-17 (also called IL-17 A) and IL-17F, two most homologous cytokines sharing similar regulations. Here we reportthat when overexpressed in 293T cells, IL-17 and IL-17F form not only homodimers but also heterodimers, which wename as IL-17A/F. Fully differentiated mouse THi cells also naturally secrete IL-17A/F as well as IL-17 and IL-17Fhomodimeric cytokines. Recombinant IL-17A/F protein exhibits intermediate levels of potency in inducing IL-6 andKC (CXCL1) as compared to homodimeric cytokines. IL-17A/F regulation of IL-6 and KC expression is dependent onIL-17RA and TRAF6. Thus, IL-17A/F cytokine represents another mechanism whereby T cells regulate inflammatoryresponses and may serve as a novel target for treating various immune-mediated diseases.

关键词： inflammation IL-17 T cells

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何为肿瘤外科学家

中华消化外科杂志 2018年第4期17卷 I0002-I0003页

作者： Charles Balch 美国德克萨斯州休斯顿md安德森癌症中心 55943

“肿瘤外科学家”一词具有许多不同的涵义。在本社论中．笔者尝试综合外科医师和其他肿瘤学方面专家观点，进一步定义该名词。

关键词：科学家肿瘤外专家观点外科医师肿瘤学