协和医大Cancer Res：卵巢癌耐药新靶标

　　

生物通报道，来自北京协和医院妇产科的潘凌亚教授研究组经过6年临床研究发现卵巢癌的一个新的耐药靶标蛋白，该研究成果文章Increased Expression of Annexin A3 Is a Mechanism of Platinum Resistance in Ovarian Cancer发布在2月15日的《Cancer Research》上。

 

文章通讯作者是来自北京协和医科大学附属协和医院妇产科潘凌亚博士，其他作者分别来自北京基础医学研究所细胞生物系以及美国国立癌症研究所。潘凌亚博士致力于妇科肿瘤、卵巢癌的应用基础研究。

 

潘凌亚研究组首次发现Annexin  A3可能是卵巢癌铂类耐药的标记蛋白，这是国际上第一个关于Annexin  A3与卵巢癌化疗耐药相关性的研究成果，Annexin  A3蛋白有望成为卵巢癌患者耐药筛选的标记物，可提示医生为卵巢癌耐药患者选择更有针对性的化疗方案。

 

研究组用比较蛋白质组学技术研究发现，Annexin  A3蛋白在全部5种卵巢癌铂类耐药细胞株中的表达明显升高。随后课题组选取了40位卵巢癌化疗患者作为研究对象，其中20位对顺铂类药物敏感，另外20位对顺铂耐药。经过免疫组化检测证实，Annexin  A3在耐药患者的组织中表达明显升高，且Annexin  A3高表达组的无瘤生存期显著缩短。  

 

研究还揭示，Annexin  A3是通过降低细胞内铂含量及铂-DNA结合量、降低卵巢癌细胞P53水平而产生耐药的。动物实验也表明，Annexin  A3高表达的细胞受顺铂作用后，其成瘤率明显上升。该项研究还发现，Annexin  A3高表达的细胞对铂类药物的耐药性明显增强，但与紫杉醇、表阿霉素等药物无交叉耐药性，提示Annexin  A3蛋白有望成为卵巢癌特异性的铂类耐药相关蛋白。

 

据介绍，Annexin是一组结构功能相似的Ca2+（钙离子）依赖性的磷脂结合蛋白，在多种生物学活动中发挥作用，目前已发现Annexin蛋白拥有13个家族成员。

（物通 小茜）

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Increased Expression of Annexin A3 Is a Mechanism of Platinum Resistance in Ovarian Cancer

Xuedong Yan1, Jie Yin1, Huiyu Yao2, Ning Mao2, Yili Yang3 and Lingya Pan1

Authors' Affiliations: 1 Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; 2 Department of Cell Biology, Institute of Basic Medical Sciences, Beijing, People's Republic of China; and 3 Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, Maryland

 

Corresponding Author: Lingya Pan, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuai Fu Yuan, Wang Fu Jing Street, Beijing 100730, China. Phone: [phone]; Fax: [phone]; E-mail: [e-mail].

 

 

Resistance to platinum drugs has emerged as a major obstacle in the treatment of ovarian cancers. Through proteomic analysis, we have found that the expression of annexin A3, a member of the Ca2+ and phospholipid-binding annexin family, is significantly increased in platinum-resistant ovarian cell lines. Anti–annexin A3 immunostaining indicated that cancers from platinum-resistant patients also possess higher levels of annexin A3 than those from platinum-sensitive patients. Although expression of annexin A3 made susceptible ovarian cancer cells more resistant to platinum, expression of antisense annexin A3 downregulated its expression and rendered the resistant cells more sensitive to platinum. In athymic mice, the growth of tumors from inoculated SKOV3 cells was inhibited by the administration of platinum, whereas tumors from annexin A3–expressing SKOV3/Ann were resistant to platinum treatment. Interestingly, the intracellular platinum concentration and platinum-DNA binding are significantly lower in annexin A3–overexpressing cells than those in parental cells. The lower cisplatin concentration was also accompanied by reduced induction of p53, which could be restored by downregulation of annexin A3. These results indicate that increased expression of annexin A3 is a mechanism of platinum resistance in ovarian cancer. It seems to act by preventing uptake or accumulation of platinum in cells. Therefore, it is conceivable that annexin A3 could be a target for therapeutic intervention and may also serve as a biomarker for drug resistance in ovarian cancer patients. Cancer Res; 70(4); 1616–24

 

潘凌亚

女，中国医学科学院北京协和医院妇产科主任医师、教授、博士生导师，科副主任。《基础医学与临床》杂志副主编，《英国医学杂志中文版》通讯编委，《国际妇科肿瘤杂志中文版》编委，《中华医学杂志》《中华老年杂志》特约审稿专家。1983年毕业于上海第二军医大学，获医学学士学位。1993年毕业于中国协和医科大学妇产科学系，获医学博士学位。1996~1997年在香港大学玛丽医院进修临床妇科肿瘤学。

 

长期从事妇产科及妇科肿瘤的临床工作，具有丰富的治疗妇产科，特别是妇科肿瘤疾病的临床经验和熟练的手术技巧。致力于妇科肿瘤、卵巢癌的应用基础研究。先后承担国家自然科学基金四项，国家卫生部基金一项，北京协和医院重点基金一项。有数十篇文章在国家核心期刊发表。先后指导10余名硕士和博士研究生。