上海交通大学学报（医学版）

›› 2011, Vol. 31 ›› Issue (1): 21-.doi: 10.3969/j.issn.1674-8115.2011.01.005

• 论著（基础研究） • 上一篇    下一篇

表皮生长因子受体信号通路在人子宫内膜癌移植瘤孕激素耐药机制中的作用

徐妍力, 王 娟, 艾志宏, 滕银成   

  1. 上海交通大学附属第六人民医院妇产科, 上海 200233
  • 出版日期:2011-01-28 发布日期:2011-02-01
  • 通讯作者: 滕银成, 电子信箱: teng1008@sohu.com。
  • 作者简介:徐妍力（1986—）, 女, 硕士生；电子信箱: xuyanli106@hotmail.com。
  • 基金资助:

    上海市科委基金（07ZR14059）；国家自然科学基金（30801229）

Role of epidermal growth factor receptor signaling pathway in progestin resistance of human endometrial carcinoma xenografts

XU Yan-li, WANG Juan, AI Zhi-hong, TENG Yin-cheng   

  1. Department of Obstetrics and Gynecology, The Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China
  • Online:2011-01-28 Published:2011-02-01
  • Supported by:

    Shanghai Science and Technology Committee Foundation, 07ZR14059；National Natural Science Foundation of China, 30801229

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摘要：

目的 建立人子宫内膜癌皮下移植瘤孕激素耐药模型，探讨表皮生长因子受体（EGFR）下游信号通路在子宫内膜癌孕激素耐药机制中的作用。方法 分别利用人子宫内膜癌孕激素敏感型Ishikawa细胞株和孕激素不敏感型Ishikawa-pLWERNL细胞株制备裸鼠皮下移植瘤模型（每组18只）；成瘤后，分别将接种Ishikawa细胞株和接种Ishikawa-pLWERNL细胞株的裸鼠各自分成3组（每组6只），分别给予甲羟孕酮（MPA组）、吉非替尼（吉非替尼组）、生理盐水（对照组）。疗程结束后称取各组肿瘤湿重，采用Western blotting法检测肿瘤组织中EGFR、孕激素受体B（PR-B）、ERK1/2、p-ERK1/2、AKT及p-AKT蛋白的表达。结果 在接种Ishikawa细胞株的裸鼠中，MPA组、吉非替尼组移植瘤湿重与对照组相比，分别减轻43.0%和31.5%，差异有统计学意义（P均<0.05）。在接种Ishikawa-pLWERNL细胞株的裸鼠中，吉非替尼组移植瘤湿重与对照组相比，减轻35.7%，差异有统计学意义（P<0.05）；而MPA组移植瘤湿重与对照组相比，减轻2.9%，差异无统计学意义（P>0.05）。接种Ishikawa-pLWERNL细胞株的裸鼠移植瘤EGFR蛋白表达明显高于接种Ishikawa细胞株的裸鼠移植瘤（P<0.05），而PR-B蛋白表达则明显低于接种Ishikawa细胞株的裸鼠移植瘤（P=0.000）。接种Ishikawa细胞株的裸鼠移植瘤中，MPA组PR-B蛋白表达明显低于对照组（P<0.01），而吉非替尼组与对照组的差异无统计学意义（P>0.05）；在接种Ishikawa-pLWERNL细胞株的裸鼠移植瘤中，各组PR-B蛋白表达水平比较差异均无统计学意义（P>0.05）。在接种Ishikawa细胞株的裸鼠移植瘤中，吉非替尼组p-ERK1/2、p-AKT蛋白表达均低于对照组和MPA组，差异有统计学意义（P<0.05）；而在接种Ishikawa-pLWERNL细胞株的裸鼠移植瘤中，吉非替尼组p-ERK1/2、p-AKT蛋白表达低于对照组，MPA组p-ERK1/2、p-AKT蛋白表达高于对照组，差异均有统计学意义（P<0.05，P<0.01）。结论 在接种孕激素不敏感型Ishikawa-pLWERNL细胞株产生的移植瘤中，过表达的EGFR可下调PR-B蛋白表达，而对MPA不敏感；EGFR受体酪氨酸激酶拮抗剂吉非替尼可有效抑制p-ERK1/2和p-AKT的表达，尤其对接种Ishikawa-pLWERNL细胞株产生的移植瘤效果更显著。

关键词: 人子宫内膜癌移植瘤, 表皮生长因子受体信号通路, 孕激素受体B, 孕激素耐药, 吉非替尼

Abstract:

Objective To establish progestin-resistant models of human endometrial carcinoma xenografts, and explore the role of epidermal growth factor receptor (EGFR) signaling pathway in progestin resistance of human endometrial carcinoma xenografts. Methods Thirty-six nude mice were subcutaneously injected with human endometrial carcinoma progestinsensitive Ishikawa cells (n=18) or progestin-insensitive Ishikawa-pLWERNL cells (n=18), and human endometrial carcinoma xenografts were formed. Then, both nude mice treated with Ishikawa cells and Ishikawa-pLWERNL cells were divided into three groups, respectively (n=6), and were managed with medroxyprogesterone acetate (MPA)(MPA group), gefitinib (gefitinib group) and normal saline (control group), respectively. After treatment, wet weight of xenografts was recorded, and the expression of EGFR, progesterone receptor B (PR-B), ERK1/2, p-ERK1/2, AKT and p-AKT protein in xenograft tissues was detected by Western blotting. Results In nude mice treated with Ishikawa cells, the wet weight of xenografts in MPA group and gefitinib group was 43.0% and 31.5% lower than that in control group, respectively (P<0.05). In nude mice treated with Ishikawa-pLWERNL cells, the wet weight of xenografts in gefitinib group and MPA group was 35.7% and 2.9% lower than that in control group, respectively (P<0.05 and P>0.05). The expression of EGFR protein in xenograft tissues treated with Ishikawa-pLWERNL cells was significantly higher than that in xenograft tissues treated with Ishikawa cells (P<0.05), while that was opposite for the expression of PR-B protein （P=0.000）. In xenograft tissues treated with Ishikawa cells, the expression of PR-B protein in MPA group was significantly lower than that in control group （P<0.01）, while there was no significant difference between gefitinib group and control group （P>0.05）. In xenograft tissues treated with Ishikawa-pLWERNL cells, there was no significant difference in the expression of PR-B protein among groups （P>0.05）. In xenograft tissues treated with Ishikawa cells, the expression of p-ERK1/2 and p-AKT protein in gefitinib group was significantly lower than that in control group and MPA group (P<0.05). In xenograft tissues treated with Ishikawa-pLWERNL cells, the expression of p-ERK1/2 and p-AKT protein in gefitinib group was significantly lower than that in control group (P<0.05), and the expression of p-ERK1/2 and p-AKT protein in MPA group was significantly higher than that in control group (P<0.01）. Conclusion The over-expressed EGFR protein can downregulate the expression of PR-B protein in Ishikawa-pLWERNL xenografts, which results in insensitivity to MPA. Gefitinib, the EGFR tyrosine kinase inhibitors, can effectively inhibit the expression of p-ERK1/2 and p-AKT protein, especially in  progestin-insensitive Ishikawa-pLWERNL xenografts.

Key words: human endometrial carcinoma xenografts, epidermal growth factor receptor signaling pathway, progesterone receptor B;progestin resistance, gefitinib