Estrogen and insulin-like growth factor 1 synergistically promote the development of lung adenocarcinoma in mice
Estrogen and insulin-like growth factor 1 synergistically promote the development of lung adenocarcinoma in mice
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DOI：
10.1002/ijc.28262
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发表时间：
2013-11-15
影响因子：
6.4
通讯作者：
Zhou, Sheng
中科院分区：
文献类型：
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作者：
Tang, Hexiao;Liao, Yongde;Zhou, Sheng
雌激素受体（ER）和胰岛素样生长因子-1受体（IGF-1 R）信号转导与肺癌进展有关。基于他们以前的发现，作者试图研究雌激素和IGF-1是否协同作用促进小鼠肺腺癌（LADE）的发展。用乌拉坦诱发去卵巢昆明小鼠LADE。将荷瘤小鼠分为7组：17-雌二醇（E2）、E2+氟维司群（Ful;雌激素抑制剂）、IGF-1、IGF-1+ AG 1024（IGF-1抑制剂）、E2 + IGF-1、E2 +IGF-1+Ful+ AG 1024和对照组。14周后处死小鼠，然后测定肿瘤生长。采用组织芯片免疫组化法检测ER/ER、IGF-1、IGF-1 R和Ki 67的表达，Western blot法检测IGF-1、p-ER、p-IGF-1 R、p-MAPK和p-AKT的表达。采用荧光定量聚合酶链反应检测ER、ER 2和IGF-1 R mRNA的表达。肿瘤发生率为93.88%（46/49），病理证实的LADE发生率为75.51%（37/49）。在E2+IGF-1组中，肿瘤生长显著高于E2组（p < 0.05）、IGF-1组（p < 0.05）和对照组（p < 0.05）。类似地，ER、p-ER、ER 2、IGF-1、IGF-1 R、p-IGF-1 R、p-MAPK、p-AKT和Ki 67在蛋白和/或mRNA水平的表达在配体组中显著高于配体+抑制剂组（均p < 0.05）。本研究首次证明雌激素和IGF-1协同促进小鼠LADE的发生，这可能与MAPK和AKT信号通路的激活有关，其中ER 1、ER 2和IGF-1 R发挥重要作用。本研究首次证实雌激素和胰岛素样生长因子-1（IGF-1）可协同促进小鼠肺腺癌的发生。这种作用可能与MAPK和AKT信号通路的激活有关，其中关键分子ER 1、ER 2和IGF-1 R起重要作用。结果进一步表明，雌激素受体（ER）和IGF-1 R抑制剂的联合使用可能会抑制肺腺癌的生长在更大程度上比单独使用任何一种抑制剂。因此，阻断雌激素和IGF-1信号通路中的多个靶点可能对肺癌具有实质性的治疗潜力。
Estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF-1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. LADE was induced with urethane in ovariectomized Kunming mice. Tumor-bearing mice were divided into seven groups: 17-estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024 (IGF-1 inhibitor), E2+IGF-1, E2+IGF-1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ER/ER, IGF-1, IGF-1R and Ki67 was examined using tissue-microarray-immunohistochemistry, and IGF-1, p-ER, p-IGF-1R, p-MAPK and p-AKT levels were determined based on Western blot analysis. Fluorescence-quantitative polymerase chain reaction was used to detect the mRNA expression of ER, ER2 and IGF-1R. Tumors were found in 93.88% (46/49) of urethane-treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF-1 group, tumor growth was significantly higher than in the E2 group (p < 0.05), the IGF-1 group (p < 0.05) and control group (p < 0.05). Similarly, the expression of ER, p-ER, ER2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT and Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p < 0.05). This study demonstrated for the first time that estrogen and IGF-1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ER1, ER2 and IGF-1R play important roles.What's new? The present study demonstrated for the first time that estrogen and insulin-like growth factor-1 (IGF-1) can synergistically promote the development of lung adenocarcinoma in mice. Such effect might be attributed to the activation of the MAPK and AKT signaling pathways, with the key molecules ER1, ER2, and IGF-1R playing important roles. The results further revealed that the combined use of estrogen receptor (ER) and IGF-1R inhibitors may suppress lung adenocarcinoma growth to a greater extent than either inhibitor alone. Blocking multiple targets in the estrogen and IGF-1 signaling pathways may thus have substantial therapeutic potential in lung cancer.