中科大校友《Molecular Cell》文章解析肿瘤相关研究

　　生物通报道：来自美卡罗莱纳州大学健康科学中心（University of Colorado Health Sciences Center），比利时鲁汶大学医学院（University of Louvain Medical School），杜克大学医学院，四川大学华西医科大学附属第二医院，上海交通大学第一人民医院的研究人员S-亚硝基化（NO-mediated S-nitrosylation）对缺氧诱导因子-1(hypoxia inducible factor 1，HIF-1)的调控作用，从而为治疗肿瘤以及哺乳动物炎症反应的治疗提出新的思路。这一研究成果公布在《Molecular Cell》（《Cell》子刊之一，影响因子16．835）。

文章的通讯作者为现任杜克大学副教授的李传元（Chuan-Yuan Li，音译），其早年毕业于中国科技大学，在哈佛大学获得了博士学位。另外参与这一研究的还有四川大学华西医科大学的严斌（Bin Yan，音译），以及上海交通大学第一人民医院的黄谦（Qian Huang，音译）。

原文摘要：
Molecular Cell, Vol 26, 63-74, 13 April 2007
Regulation of HIF-1α Stability through S-Nitrosylation
[Abstract]

缺氧诱导因子-1(hypoxia inducible factor 1，HIF-1)是调节肿瘤细胞缺氧反应的主要转录因子，在正常的氧气压力下，HIF-1的活性通常取决于其两个亚单位之一：HIF-1α。HIF-1α在许多肿瘤中表达增强，与肿瘤高度侵袭性、易转移、对放化疗不敏感和预后不良密切相关，而且能促进血管内皮生长因子(vascular endothelial growth factor,VEGF)依赖性的肿瘤血管形成和增强肿瘤细胞糖酵解(Warburg效应)，因此以HIF-1α为靶点的抗肿瘤治疗正成为许多基础和临床研究的热点。

在这篇文章中，研究人员报道了NO介导的S-亚硝基化（NO-mediated S-nitrosylation）和HIF-1α稳定性可以正调控常氧（normoxic）HIF-1的活性。同时研究人员也发现将鼠科动物肿瘤暴露电离辐射（ionizing radiation）下，会刺激肿瘤相关巨噬细胞的NO的产生，从而HIF-1α在氧依赖降解结构域(oxygen—dependent degradation domain，ODD)的Cys533（通过“biotin switch”分析）发生S-亚硝基化。重要的是，这种机制可能是与prolylhydroxylase-based途径（HIF-1α氧依赖性调控相关）是不相关的。研究人员认为这种在NO和HIF-1之间的相互作用能够给肿瘤以及哺乳动物炎症反应的治疗提出新的思路。
（生物通：张迪）

附：
Chuan Yuan Li
Assistant Professor, Department of Radiation Oncology,Duke University Medical Center

教育：
B.Sc. in Chemistry, University of Science and Technology, Hefei, China, 1987
Ph.D. in Cancer Biology, Harvard University, Cambridge, MA, 1993


专业学术经历：

1993-1997: Postdoctoral Research Fellow, Department of Cancer Biology, Harvard University School of Public Health.
1997-present: Present: Assistant Professor of Radiation Oncology/Biology, Duke University Medical Center.

发表文章：

1. Li, C-Y., Yandell, D.W., and Little, J.B.(1992) Molecular Mechanisms of Spontaneous and Induced Loss of Heterozygosity in Human Cells In Vitro. Somatic Cell and Molecular Genetics, 18: 77-87

2. Li, C-Y., Yandell, D.W., and Little, J.B. (1992) Evidence for Coincident Mutations in Human Lymphoblast Clones Selected for Functional Loss of a Thymidine Kinase Gene. Molecular Carcinogenesis, 5:270-277

3. Spiro, I. J., Yandell, D.W., Li, C-Y. , Saini, S., Ferry, J., Powelson J., Katkov, W.N., and Cosimi, A.B (1993). Lymphoma of Donor Origin Occuring at the Porta Hepatis of Transplanted Liver. New England Journal of Medicine, 329:27-29

4. Poremba, C., Dockhorn-Dworniczak, B., Merrit, V., Li, C-Y. (1993) Heidle, G., Tauber, P., Bocker, W., , and Yandell, D.W. Immature Teratomas of Different Origin Carried by a Pregnant Mother and Her Fetus. Diagnostic Molecular Pathology , 2:131-136

5. Li, C-Y., Yandell, D.W., and Little, J.B. (1994) Elevated frequency of Microsatellite Mutations in Human Lymphoblast Clones Selected for Mutations at Thymidine Kinase locus. Molecular & Cellular Biology , 14:4373-4379

6. Li, C-Y., Nagasawa, H., Tsang, N., and Little, J.B. (1995) Radiation-Induced Irreversible G0/G1 Block is Abolished in Human Diploid Fibroblasts Transfected with the Human Papilloma Virus E6 gene: Implication of the p53-Cip1/WAF1 pathway. International Journal of Oncology, 1 : 223-236

7. Li, C-Y., Suardet, L., and Little, J.B. (1995) Potential Role of WAF1/Cip1/p21 as a Mediator of TGF-b Cytoinhibitory Effect . Journal of Biological Chemistry 270:4971-4974

8. Nagasawa, H., Li, C-Y., Maki, C.G. , Imrich A. and Little, J.B. (1995) Relationship between Radiation-Induced G1 Phase Arrest and p53 Function in Human Tumor Cells Cancer Research 55:1842-1846.

9. Little, J.B. , Nagasawa, H., Keng, P., and Li, C-Y. Absence of Radiation-induced G1-arrest in Two Closely Related Human Lymphoblast Cell Lines That Differ in p53 Status Journal of Biological Chemistry 270:11033-11036.

10. Tsang, N., Nagasawa, H., Li, C-Y., and Little, J.B. Abrogation of p53 function by Transfection of HPV16 E6 Gene Enhances the Resistance of Human Diploid Fibroblasts to Ionizing Radiation Oncogene 10:2403-2408.

11. Li, C-Y., Nagasawa, H., Dahlberg, W.A., and Little, J.B. (1995) Published Capacity for p53 in Mediating a Radiation-Induced G1 Arrest in Established Human Tumor Cell Lines Oncogene :1885-1892.

12. Little, J.B., Li, C-Y., Nagasawa, H., Pfenning, T., and Vetrovs, H. Genomic Instability and Radiation Mutagenesis (1996) J. Chimie Phys. 93:157-164

13. Li, C-Y., Nagasawa, H., Dahlberg, W.A., and Little, J.B. (1996) The Role of Tumor Suppressor Genes in Determining a Radation-induced G1-arrest and Human Cell Carcinogenesis Radiation Oncology Investigations, 3:268-271.

14. Huang, H-M., Li, C-Y, Little, J.B. (1996) Abrogation of p53 Function in Human Tumor Cells Does Not Alter Their Sensitivity to Ionizing Radiation. International Journal of Radiation Biology, 70:151-160.

15. Suardet, L., Li, C-Y., and Little J.B. (1996) Radio-induced modulation of transforming growth factor sensitivity in a p53 wild-type human colorectal cancer cell line . International Journal of Cancer 68:126-31.

16. Yu, Y., Li, C-Y., Little, J.B. (1997) Abrogation of p53 function by HPV16 E6 gene delays apoptosis and enhances mutagenesis but does not alter radiosensitivity in TK6 human lymphoblastoid cells. Oncogene, 14:1661-1667.

17. Huang, Q., Shan, S, Braun, R.D., Lanzen, J., Anyrhambatla, G., Kong, G., Borelli, M., Corry, P., Dewhirst, M.W., and Li, C-Y. (1999) GFP based non-invasive, in vivo monitoring of gene expression. Nature Biotechnology, 17: 1033-1035.

18. Li, C-Y., Shan, SQ., Huang, Q., Braun, R.D., Lanzen, J., Turnage, J., Dewhirst, M.W. (2000) Initial stages of tumor cells-induced angiogenesis:evaluation via skin window chambers in rodent models Journal of the National Cancer Institute, 92:143-127

19. Huang,Q., Hu, K., Lohr, F., Zhang,L., Braun, R., Lanzen, J., Little,JB., Dewhirst, MW., and Li, C-Y. (2000) Heat-induced Gene Expression as a Novel Targeted Cancer Gene Therapy Strategy Cancer Research, In Press.