Hospicells promote upregulation of the ATP-binding cassette genes by insulin-like growth factor-I via the JAK2/STAT3 signaling pathway in an ovarian cancer cell line.
Hospicells promote upregulation of the ATP-binding cassette genes by insulin-like growth factor-I via the JAK2/STAT3 signaling pathway in an ovarian cancer cell line.
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DOI：
10.3892/ijo.2013.2017
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发表时间：
2013-09
影响因子：
5.2
通讯作者：
Mirshahi M
中科院分区：
文献类型：
--
作者：
Benabbou N;Mirshahi P;Cadillon M;Soria J;Therwath A;Mirshahi M
肿瘤细胞与其微环境的相互作用在肿瘤的发生、发展和耐药过程中起着至关重要的作用。我们的目的是确认Hospicells（一种来自癌症微环境的基质细胞）在耐药和肿瘤细胞生长中的作用。在卵巢癌细胞系中，由Hospicells分泌的可溶性因子激活多个基因，上调JAK/STAT信号通路。通过基因阵列、RT-PCR、蛋白阵列和免疫细胞化学检测，Hospicells表达所有胰岛素样生长因子（IGF）家族。在关注微环境的同时，我们考虑了igf - 1在卵巢癌细胞增殖和存活中的作用。事实上，igf - 1是癌症发展不同阶段的主要调节因子。我们研究了外源添加IGF-I对卵巢癌细胞系OVCAR3中atp结合盒（ABC）基因（MDR1、MRP1、MRP2、MRP3、MRP5和BCRP）的调控作用，并使用IGF-IR拮抗剂微肽卟卟肽验证了结果。IGF-I通过pi3激酶、MEK和JAK2/STAT3信号通路调控OVCAR3细胞中ABC基因的表达。OVCAR3细胞系与Hospicells共培养时显示出明显的耐药程度。外源性igf - 1可扩增所观察到的耐药性。然而，添加IGF-IR抑制剂可降低这些暴露细胞的耐药程度。用抗癌药物治疗的细胞，然后暴露于igf - 1，显示出耐药性的增加，从而增加了细胞存活率。这一观察结果表明，OVCAR3细胞与Hospicells协同作用时，OVCAR3细胞的耐药能力增强，外源添加IGF-I时，OVCAR3细胞的耐药能力增强。总之，抑制IGF-IR和靶向JAK2/STAT3信号通路可以作为卵巢癌治疗的靶点。
Interaction between tumor cells and their microenvironment has a crucial role in the development, progression and drug resistance of cancer. Our objective was to confirm the role of Hospicells, which are stromal cells from the cancer microenvironment, in drug resistance and tumor cell growth. We demonstrated that soluble factors secreted by Hospicells activate several genes and upregulate the JAK/STAT signaling pathway in ovarian cancer cell lines. Hospicells express all insulin-like growth factor (IGF) family as detected by gene array, RT-PCR, protein array and immunocytochemistry. While focusing attention on the microenvironment, we considered the role of IGF-I in proliferation and survival of ovarian cancer cells. Indeed, IGF-I is a major regulator of different stages of cancer development. We studied the effect of exogenously added IGF-I on the regulation of ATP-binding cassette (ABC) genes (MDR1, MRP1, MRP2, MRP3, MRP5 and BCRP) in the ovarian cancer cell line OVCAR3 and validated the results obtained using the IGF-IR antagonist picropodophyllin. IGF-I regulates the expression of ABC genes in OVCAR3 cells via the PI3-kinase, MEK and JAK2/STAT3 signaling pathways. The OVCAR3 cell line when co-cultured with Hospicells showed a marked degree of drug resistance. The drug resistance observed could be amplified with exogenous IGF-I. Addition of IGF-IR inhibitor, however, reduced the degree of resistance in these exposed cells. Cells that were treated with anticancer drugs and then exposed to IGF-I showed an increase in drug resistance and, thereby, an increase in cell survival. This observation indicates that drug resistance of OVCAR3 cells increases when there is synergy between OVCAR3 cells and Hospicells and it is amplified when IGF-I was exogenously added. In conclusion, inhibition of IGF-IR and targeting of the JAK2/STAT3 signaling pathway can be a target for ovarian cancer therapy.
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影响因子：
4.7
作者：
Hu, Chen;Li, Hong;Gu, Jianren
通讯作者：
Gu, Jianren
DOI：
10.1093/jnci/djn389
发表时间：
2008-12-03
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Jemal A;Thun MJ;Ries LA;Howe HL;Weir HK;Center MM;Ward E;Wu XC;Eheman C;Anderson R;Ajani UA;Kohler B;Edwards BK
通讯作者：
Edwards BK
影响因子：
20.3
作者：
Dankbar, B;Padró, T;Kienast, J
通讯作者：
Kienast, J
DOI：
10.1155/2010/430939
发表时间：
2010-01-01
期刊：
Metal-Based Drugs
影响因子：
--
作者：
Chen, Helen H. W.;Kuo, Macus Tien
通讯作者：
Kuo, Macus Tien
影响因子：
2.2
作者：
Sako, A;Kitayama, J;Nagawa, H
通讯作者：
Nagawa, H