癌相关成纤维细胞通过Gro-α激活NF-кB核转位和VEGF表达促进卵巢癌的生长

doi:10.3969/j.issn.1007-3969.2014.05.001

中国癌症杂志 ›› 2014, Vol. 24 ›› Issue (5): 321-328.doi: 10.3969/j.issn.1007-3969.2014.05.001

癌相关成纤维细胞通过Gro-α激活NF-кB核转位和VEGF表达促进卵巢癌的生长

任春霞¹,徐娜¹,宋亚琴¹,赵敏²,陈亚萍³,吕蓓¹,杨恭^4,5

1.江苏省无锡市人民医院妇产科，江苏无锡 214023；
2.山东省交通医院妇产科，山东济南 250031；
3.复旦大学附属上海市第五人民医院妇产科，复旦大学上海医学院妇产科学系，上海 200240；
4.复旦大学附属上海市第五人民医院中心实验室，复旦大学上海医学院妇产科学系，上海 200240；
5.复旦大学附属肿瘤医院肿瘤研究所，复旦大学上海医学院肿瘤学系，上海 200032

出版日期:2014-05-30 发布日期:2014-05-26
通信作者: 吕蓓　E-mail:lvbei@wuxiph.com
基金资助:
南京医科大学面上基金(No：2012NJMU179)；国家自然科学基金面上项目(No：NSFC91129721)

Promotion of ovarian tumorigenesis by cancer-associated fibroblasts through Gro-α activated NF-кB nuclear translocation and high expression of VEGF

REN Chun-xia¹, XU Na¹, SONG Ya-qin¹, ZHAO Min², CHEN Ya-ping³, LV Bei¹, YANG Gong^{4, 5}

1.Department of Gynecology and Obstetrics, The People’s Hospital of Wuxi, Wuxi Jiangsu 214023, China;
2.Department of Gynecology and Obstetrics, Shandong Jiao Tong Hospital, Jinan Shandong 250031, China;
3.Department of Gynecology and Obstetrics, The Fifth People’s Hospital of Shanghai, Fudan University; Department of Gynecology and Obstetrics, Shanghai Medical College, Fudan University Shanghai 200240, China;
4.Central Laboratory, The Fifth People’s Hospital of Shanghai, Fudan University; Department of Gynecology and Obstetrics, Shanghai Medical College, Fudan University Shanghai 200240, China;
5.Cancer Institute, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Published:2014-05-30 Online:2014-05-26
Contact: LV Bei E-mail: lvbei@wuxiph.com

摘要/Abstract

摘要： 背景与目的：卵巢癌相关成纤维细胞(cancer-associated fibroblasts，CAF)促进上皮肿瘤的发生，其分泌的趋化因子即生长调节致癌基因α(growth-regulated oncogene alpha，Gro-α)蛋白在肿瘤间质微环境中促进上皮卵巢癌的发生，但其作用机制并不清楚。本研究拟测定Gro-α蛋白是否通过激活间质成纤维细胞中NF-кB核转位和VEGF表达，促进卵巢癌的生长。方法：本研究采用ELISA法测定了两株卵巢癌CAF和两株正常卵巢组织成纤维细胞(normal fibroblasts，NF)条件培养基(conditioned medium，CM)中Gro-α的表达；用CAF-CM或Gro-α分别处理NF，并以NF-кB抑制剂处理作为对照；用蛋白质印迹法(Western blot)测定样品处理前后NF-кB和血管内皮细胞生长因子(vascular endothelial growth factor，VEGF)等分子的变化；然后用CAF或NF分别与卵巢癌细胞系OVCA429混合接种BALB/c裸小鼠，或在有、无NF-кB抑制剂PS1145处理的NF中，用CAFCM或Gro-α处理后，分别与OVCA429混合接种动物，观察和比较动物移植瘤生长及移植瘤组织中微血管形成情况。结果：Gro-α在CAF中比在NF中高5～6倍；与对照组相比，用CAF条件培养基或Gro-α处理的NF中NF-кB p65的核转位升高，且VEGF上升，但血管生成抑制因子-血小板反应蛋白1下降；用NF-кB抑制剂同时处理NF，可以逆转其VEGF和TSP-1的表达水平；动物试验结果发现CAF要比NF更易促进肿瘤生长，而CAF-CM或Gro-α处理的NF细胞可以促进动物移植瘤的快速增长和移植瘤组织中微血管的生成，但用NF-кB抑制剂处理的NF则抑制肿瘤生长和血管形成能力。结论：卵巢癌CAF在肿瘤微环境中通过自分泌Gro-α，激活NF-кB核转位和VEGF表达，促进卵巢癌组织血管增生和肿瘤的生长。

Abstract:

Background and purpose: Ovarian cancer-associated fibroblasts (CAF) are known to promote epithelial malignancy. The chemoattractant cytokine growth-regulated oncogene alpha (Gro-α) secreted from CAF has been reported to mediate the stroma-epithelia interaction in tumor microenvironment, leading to the development of epithelial ovarian cancer, however, the detailed mechanism is unknown.This study was to determine whether Gro-α could promote ovarian tumorigenesis through activating NF-кB nuclear translocation and VEGF expression in stromal fibroblasts. Methods: ELISA was used to measure the levels of Gro-α in two cancer-associated fibroblasts (CAF) and normal fibroblasts (NF) isolated from high-grade serous ovarian cancer or normal ovarian tissues. CAF conditioned medium (CM) or Gro-α was used to treat NF, while PS1145, the inhibitor of NF-кB, was used as control. NF-кB subunit p65 and vascular endothelial growth factor (VEGF) were detected by Western blot in cells after treatment. Xenograft tumors from nude mice were generated by injection of CAF, NF, or OVCA429 alone or OVCA429 mixed with CAF or NF, and by injection of OVCA429 mixed with NF cells that were treated with or without CAF-CM or Gro-α, or with NF cells that were treated with CAF-CM or Gro-α plus PS1145. The tumor growth curve was measured and the blood vessel density in xenograft tumor tissues was examined by histopathological analysis. Results: The levels of Gro-α were 5-6 folds higher in CAF than in NF. Treatment of NF with CAF-CM or Gro-α stimulated the nuclear translocation of NF-кB subunit p65, and the expression of VEGF, but suppressed the expression of thrombospondin 1, the antiangiogenesis factor, compared with control cells. However, treatment of NF with the NF-кB inhibitor PS1145 reversed these results. The animal assay revealed that CAF stimulated tumor growth stronger than NF, and NF treated with CAF-CM or Gro-α, but not along with PS1145, enhanced xenograft tumor growth through promoting angiogenesis. Conclusion: Ovarian CAF promotes the nuclear translocation of NF-кB and the expression of VEGF through Gro-α autocrine in tumor microenvironment to facilitate angiogenesis and ovarian cancer development.

Key words: Cancer-associated fibroblasts, Gro-α, NF-кB nuclear translocation, Vascular endothelial growth factor, Ovarian cancer

任春霞,徐娜,宋亚琴,赵敏,陈亚萍,吕蓓,杨恭. 癌相关成纤维细胞通过Gro-α激活NF-кB核转位和VEGF表达促进卵巢癌的生长[J]. 中国癌症杂志, 2014, 24(5): 321-328.

REN Chun-xia, XU Na, SONG Ya-qin, ZHAO Min, CHEN Ya-ping, LV Bei, YANG Gong. Promotion of ovarian tumorigenesis by cancer-associated fibroblasts through Gro-α activated NF-кB nuclear translocation and high expression of VEGF[J]. China Oncology, 2014, 24(5): 321-328.

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癌相关成纤维细胞通过Gro-α激活NF-кB核转位和VEGF表达促进卵巢癌的生长

Promotion of ovarian tumorigenesis by cancer-associated fibroblasts through Gro-α activated NF-кB nuclear translocation and high expression of VEGF

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