徐燕博士简介

徐燕 博士，资深研究员 Yan Xu, Ph.D., Investigator, National Institute of Biological Sciences, Beijing. 电话（Tel）：010-80726688 传真（Fax）：010－80726689 E-mail：xuyan@nibs.ac.cn

教育经历Education
1982年 北京师范大学生物系学士
B.S. Biology, 1982,
Beijing Normal University, Beijing, China
1988年 纽约州立大学奥尔巴尼分校生物化学博士
Ph.D. Biochemistry, 1988,
The State University of New York at Albany, NY, USA
工作经历Professional Experience
2004-present National Institute of Biological Sciences, Beijing, China（中国北京生命科学研究所工作）
2003-Present Associate Professor, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University（Case Western Reserve大学Cleveland临床医学院分子医学系副教授）
2000-Present Associate Staff, Department of Gynecology & Obstetrics in the Division of Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio（Cleveland临床医学基金会、外科妇产科助理）
2000-Present Associate Staff, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio（Cleveland临床医学基金会、Lerner研究所助理）
1997-1999 Assistant Staff, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio（Cleveland临床医学基金会、Lerner研究所助理）
1993-1997 Project Scientist, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio（Cleveland临床医学基金会、Lerner研究所项目科学家）
1991-1993 Postdoc, Allelix Biopharmaceuticals, Inc., Mississauga, Ontario, Canada（Allelix Biopharmaceuticals, Inc博士后）

1988-1991 Postdoc, The Hospital for Sick Children, Toronto, Canada（多伦多残障儿童医院博士后）
研究概述：
我主要的兴趣是研究卵巢癌，乳腺癌，前列腺癌和其他恶性肿瘤发生，发展的分子机制。包括发现这些癌症的有效的诊断生物标记和预后的生物标记，确定新的治疗靶标，发展先的治

疗方法。我们率先在卵巢癌中研究了信号脂类分子的作用，已经鉴定了第一个脂类生长因子--溶血磷脂酸（lysophosphatidic acid LPA),发现LPA参与了卵巢肿瘤细胞的增殖，生存，迁移，侵袭，和转移。另外，我们还证明了LPA是一个可以用于卵巢癌早期发现的潜在的标记物。我们发展了一种高效的方法，可以来分析体液中的溶血磷脂。用这种方法我们发现，在卵巢癌病人的血液，腹水，腹膜洗液中，一些特定的有生物活性的溶血磷脂的含量升高了。当前，我们已经把这种研究扩展到乳腺癌，前列腺癌，结肠癌。我们研究了LPA以及与其相关的一些脂类信号分子比如S1P(sphingosine-1-phospahe), SPC(sphingosylphosphorylcholine), LPC(lysophosphatidylcholine)在肿瘤细胞中的作用和信号传导的机制，希望能为癌症的治疗鉴定出新的治疗靶点。我们的研究用了生物化学，分子生物学，肿瘤生物学，分析生物化学，细胞生物学遗传学等领域中的各种技术。当前，我们同时进行体外（细胞培养）和体内（小鼠模型）的研究。我们已经发现了两个脂类分子，SPC和LPC的受体。溶血磷脂和其他小的生物活性分子可以通过G蛋白偶连受体（GPCR)起作用。越来越多的证据表明，很多疾病，比如癌症，与GPCR的结构与功能的异常有关。
克隆和鉴定新的GPCR将有助于我们更好的理解这些受体的正常功能和信号传导机制，以及它们在癌症中的作用。GPCRs蕴涵着药物发现的重大希望。现在50%的药物都是以GPCR为靶标的。我们已经坚定了三种GPCR，OGR1,GPR4和G2A，它们是SPC或者LPC的受体。血管发生对于许多生理和病理过程是非常关键的。我们最近发现SPC能够在体内诱导血管的发生。SPC的高亲和性受体GPR4对于SPC在内皮细胞中起作用是必需的。在人脐静脉内皮细胞中，GPR4的下调，特异性得抑制SPC(不是S1P, 或者血管内皮生长因子）诱导的血管生成。而重新导入GPR4基因，又可以完全恢复SPC的活性。通过SPC依赖或者SPC不依赖的途径，GPR4在微血管内皮细胞的存活，生长，迁移和血管的形成中，发挥了重要的作用。SPC/GPR4的相互作用激活了phosphatidylinositol-3激酶和Akt。SPC在内皮细胞中发挥作用需要SPC诱导的转磷酸化激活VEGF受体2。这些结果确定了SPC及其受体,GPR4是内皮细胞血管发生的关键调节因子。最近，我们发现OGR1在肿瘤转移中起了重要作用。信号脂类分子领域是一个新兴令人兴奋的领域。我们已经做了一些开拓性的工作，把这些脂类分子跟卵巢癌和其它癌症联系起来。我们将继续在这一领域做一些前沿的研究工作，已期能够更好得了解肿瘤的发生，并能够提供新的诊断和预后的临床工具，治疗靶点和试剂。
Research Description：
My main research interests deal with understanding at the molecular level the mechanism of development and progress of the molecular aspects of ovarian, prostate, colon and other cancers. In particular, we are interested in tumor metastasis and angiogenesis. These include developing effective diagnostic and prognostic biomarkers for these diseases, studying signaling mechanistic studies, identifying novel therapeutic targets and methods to treat them.
We have pioneered research in the role of signaling lipid molecules in ovarian cancer and identified the first receptors for SPC and LPC:
• We have identified the first lipid growth factor in ovarian cancer cells—We have purified and identified a factor in ascites from ovarian cancer patients and have termed it ovarian cancer activating factor, or OCAF. The most striking feature of this factor is that it is not a peptide factor, but a lipid molecule. OCAF is composed of several species of lysophosphatidic acid (LPA). OCAF/LPA is 

sufficient to induce proliferation of ovarian and breast cancer cells as assayed by [3H]thymidine incorporation, MTT dye reduction or colony formation.
• We have first demonstrated that LPA is a potential marker for the early detection of ovarian cancer—We have found that LPA levels are significantly elevated in plasma from patients with ovarian and other gynecological cancers, but not from patients with breast cancer or leukemia compared with normal healthy controls. Particularly, LPA levels were also elevated in plasma from patients with early stage ovarian cancer where levels of CA 125, the most commonly used ovarian cancer marker, are often not elevated. Moreover, LPA was not detected in plasma from patients with benign gynecological disease, where CA 125 levels are often elevated. Therefore, LPA may represent a more sensitive and specific marker than CA 125 for the early detection of ovarian and other gynecological carcinomas.
• We have developed a highly effective method to analyze lysophospholipids in body fluids and shown that certain bioactive lysophospholipids are elevated in blood, ascites, and peritoneal washings from patients with ovarian cancer—Recently, we have developed an electrospray ionization mass spectrometry (ESI-MS)-based assay for detection and quantification of LPA and closely related lysophospholipids. This method can reproducibly detect various lipid species simultaneously with high sensitivity. Using this method, we detected alkyl-LPAs and alkenyl-LPAs for the first time in human body fluids (ascites from patients with ovarian cancer). We also detected SPC and other lysolipids in ovarian cancer ascites. Most importantly, these bioactive lysolipids are elevated in blood and ascitic fluids from patients with ovarian cancer, but not in normal healthy controls or patients with non-malignant diseases. These findings suggest that these lipid molecules are likely to be pathologically relevant to ovarian cancer.
• We have investigated the role and signaling mechanisms of S1P, SPC, LPA, and other lysophospholipids in ovarian cancer development. In addition, we have successfully employed the Clontech PCR-select cDNA subtraction kit and Affymetrix GeneChip in identification of genes up- or down regulated by LPA, S1P, and SPC.
• Identification of the first receptors for SPC and LPC—Lysophospholipids and other small bioactive molecules function through G protein coupled receptors (GPCRs). There is increasing evidence that abnormalities in the structure and function of GPCRs are responsible for many diseases, including cancers. Molecular cloning and characterization of novel GPCRs will contribute to a better understanding of the normal functioning and signaling mechanisms of these receptors, as well as the role that these receptors play in cancer. GPCRs hold enormous promise for therapeutic drug discovery, since about 50% of all existing pharmacenticals are targeted towards GPCRs. In an effort to identify GPCRs in ovarian cancer cells, we have cloned a novel G protein coupled receptor gene (ovarian cancer G protein coupled receptor 1, or OGR1) from HEY ovarian cancer cells by degenerate oligonucleotide PCR amplification. We have shown that SPC is a high-affinity ligand for OGR1 through calcium mobilization, ligand binding, receptor internalization, MAP kinase, and cell proliferation assays. LPC has been recognized to play an important role in human systemic autoimmune disease and atherosclerosis. G2A is
 

an orphan G protein-coupled receptor expressed predominantly in lymphocytes. Genetic ablation of G2A function in mice results in the development of autoimmunity associated with hyperproliferative responses of T lymphocytes to antigen receptor stimulation. We have shown recently that G2A is a high-affinity receptor for LPC and this work is published in Science. Science also published a Perspective article describing the importance of our finding (Science 293, 618, 2001). More recently, we have identified an OGR1-related GPCR, GPR4, as not only another high affinity receptor for SPC, but also a receptor for LPC, albeit with a lower affinity. Calcium mobilization, ligand binding, receptor internalization, MAP kinase activation, cell proliferation, and cell migration assays were conducted to establish the ligand-receptor relationship.

We will continue to: 1) investigate the role and signaling mechanisms of LPA, LPC, and SPC and their receptors in cancer and other diseases; 2) determine the structure-function relationship of the OGR1-subfamily receptors and establish molecular models of these receptors for drug development; and 3) determine the physiological and pathological roles and functions of OGR1-subfamily receptors using mouse knockout models.
发表文章Publications:
1. Xu Y., Salerno J.C., Wei Y.H., and King T.E. (1987) Stabilized Ubisemiquinone in Reconstituted Succinate Ubiquinone Reductase. Biochem. Biophys. Res. Commun. 144: 315-322.
2. Salerno J.C., Xu Y., Osgood M.P., Kim C.H., and King T.E. (1989) Thermodynamics and Spectroscopic Characteristics of the Cytochrome bc1 Complex. J. Biol. Chem. 264: 15398-15403.
3. Xu Y., Petersen-Bjorn, S., and Friesen, J. D. (1990) The PRP4 (RNA4) Protein in Saccharomyces cerevisiae is associated with the 5' Portion of the U4 snRNA. Mol. Cell. Biol. 10: 1217-1225.
4. Hu J., Xu Y., Schappert K., Harrington T., Wang A., Braga R., Mogridge J., and Friesen J.D. (1994) Mutational Analysis of the PRP4 Protein of Saccharomyces cerevisiae Suggests Domain Structure and snRNP Interactions. Nucleic Acid Res. 22: 1724-1734.
5. Hu J., Xu D., Shappert K., Xu Y., and Friesen J.D. (1995) Mutational Analysis of Saccharomyces cerevisiae U4 snRNA Identifies Functionally Important Domains, Mol. Cell Biol. 15:1274-1285.
6. Xu Y., Casey G. and Mills G. (1995) Effects of Lysophospholipids on Signaling in the Human Jurkat Cell Line. J. Cell. Physiology 163: 441-450.
7. Xu Y., Fang X-J., Casey G., and Mills G.B. (1995) Lysophospholipids Activate Ovarian and Breast Cancer Cells. Biochem. J. 309: 933-940.
8. Xu Y., Gaudette D.C., Boynton J., Frankel A., Fang X-J., Sharma A., Hurteau J., Casey G., Goodbody A.E., Mellors A., Holub B.J., and Mills G. (1995) Characterization of an 

Ovarian Cancer Activating Factor (OCAF) in Ascites from Ovarian Cancer Patients. Clinical Cancer Res. 1: 1223-1232.
9. Xu Y., and Casey G. (1996) Identification of human OGR1, a novel G protein coupled receptor that maps to the chromosome 14. Genomics 35: 397-402.
10. Xu, Y., Shen, Z., Wiper, DW., Wu. M., Morton, RE., Elson, P., Kennedy, AW., Belinson, J., Markman, M. and G. Casey (1998) Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA 280(8): 719-723.
11. Shen, Z., Belinson, J., Morton, RE., Xu, Y., and Y. Xu. (1998) PMA stimulates LPA secretion from ovarian and cervical cancer cells, but not from breast cancer and leukemia cells. Gynecol.Oncol. 71, 364-368.
12. Nugent, D., Belinson, JL., Xu, Y. (1999) The synergistic interactions of oleoyl-lysophosphatidic acid in platelet aggregation. Medical Science Research 27: 435-441.
13. Hong, G., Baudhuin, LM., Xu, Y. (1999) Sphingosine-1-phosphate modulates growth and adhesion of ovarian cancer cells. FEBS Lett 460: 513-518.
14. Xiao Y, Chen Y, Kennedy AW, Belinson J, Xu Y. (2000) Evaluation of plasma lysophospholipids for diagnostic significance using electrospray ionization mass spectrometry (ESI/MS) analyses. Ann. N.Y. Acad. Sci. 905, 242-259.
15. Schwartz BM, Hong, G, Morrison BH, Wu W, Baudhuin LM, Xiao Y. and Xu Y. (2001) Lysophospholipids Increase Interleukin-8 (IL-8) Expression in Ovarian Cancer Cells. Gyn Oncol 81, 291-300.
16. Xu, Y., Zhu K, Hong G, Wu W, Baudhuin LM, Xiao Yj, Damron DS. (2000) Sphingosylphos-

phorylcholine is a ligand for ovarian cancer G-protein-coupled receptor1. Nat Cell Biol. 2, 261-267.
17. Nugent D, Xu Y. (2000) Sphingosine-1-phosphate: characterization of its inhibition of platelet aggre-
gation. Platelets 11, 226-232.
18. Xiao Y, Schwartz B, Washington M, Kennedy A, Webster K, Belinson J. and Xu Y. (2001) Electrospray Ionization Mass Spectrometry Analysis of Lysophospholipids in Human Ascitic Fluids: Comparison of the Lysophospholipid Contents in Malignant vs. Non-malignant Ascitic Fluids. Anal Biochem 290, 302-313.
19. Xu Y, Xiao, Y, Baudhuin LM, Schwartz BM. (2001) The role and clinical applications of bioactive lysolipids in ovarian cancer. J. Soc. Gyn. Invest 8,1-13.
20. Kabarowski JHS, Zhu K, Le LQ, Witte ON, and Xu Y. Lysophosphatidylcholine as a Ligand for the Immunoregulatory Receptor G2A. Science 293, 702-705 2001
 

21. Shen Z, Wu M, Elson P, Belinson J, Kennedy A, Markman M, Casey G, Xu Y. (2001) Comparison of fatty acid compositions in plasma lysophosphatidic acid from patients with cancers and healthy women controls. Gyn. Oncol. 83, 25-30.

22. Zhu K, Baudhuin LM, Hong G, Xu Y. (2001) Sphingosylphosphorylcholine (SPC) and lysophosphatidylcholine (LPC) are ligands for GRP4. J. Biol. Chem. 276, 41325-41335.
23. Xu Y. Sphingosylphosphorylcholine and lysophosphatidylcholine: G protein coupled receptors and receptor-mediated signal transduction. Biochem Biophy Acta, 1582, 81-88, 2002.
24. Lu J, Baudhuin LM, Hong G, and Xu, Y. Role and Signaling Pathways of Ether-linked Lysophosphatidic Acids in Ovarian Cancer Cells. J. Lipid Res. 43, 463-476, 2002. 25. 26. 27. 28. 29. 30. 31.
Baudhuin LM, Kristina KL, Lu, J, and Xu Y. Activation induced by LPA and S1P requires both MEK and p38 MAP kinase and is cell-line specific. Mol Pharm. 62, 660-671, 2002.
Xu Y, Xiao Y, Zhu K, Baudhuin LM, Lu J, Hong G, Kim KS, Cristina KL, Song L, Williams FS, Elson P, Markman M, and Belinson J. Unfolding the pathophysiological role of bioactive lysophospholipids. Current drug targets-immune, endocrine & metabolic disorders. 3, 23-32, 2003
Baudhuin LM, Xiao Y, and Xu Y. SPC/LPC Receptors. In: Handbook of Cell Signaling, (Bradshaw RA and Dennis E, eds) Academic Press, San Diego, in press, 2002.
Kirsten Lauber, Erwin Bohn, Stefan-Martin Kröber, Yi-jin Xiao, Sibylle G. Blumenthal, Ralph K. Lindemann, Patrizia Marini, Shairaz Baksh, Klaus Schulze-Osthoff, Yan Xu, Ingo B. Autenrieth, Kodimangalam S. Ravichandran, Claus Belka, Gernot Stuhler, Sebastian, Wesselborg. Apoptotic cells induce migration of phagocytes via caspase-3 mediated release of a lipid attraction signal. Cell 113, 717-730, 2003.
Sengupta S, Xiao Y, and Xu Y. A novel laminin-induced LPA autocrine loop in the migration of ovarian cancer cells. FASEB J. June 3, 10.1096/fj.02-0963. 2003.
Sengupta S, Xiao YJ, Xu Y. A novel laminin-induced LPA autocrine loop in the migration of ovarian cancer cells. FASEB J. 17, 1570-1572. 2003.
Baudhuin LM, Jiang, Y, Alexander Zaslavsky, and Xu Y. S1P3-mediated Akt activation and crosstalk with platelet-derived growth factor receptor (PDGFR). FASEB J. express article 10.1096/fj.03-0302fje. Published online Dec. 4, 2003