Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL-8 production in pancreatic cancer
Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL-8 production in pancreatic cancer
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DOI：
10.3892/or.2019.7105
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发表时间：
2019-06-01
期刊：
影响因子：
4.2
通讯作者：
Takiguchi, Shuji
中科院分区：
文献类型：
--
作者：
Imafuji, Hiroyuki;Matsuo, Yoichi;Takiguchi, Shuji
吉西他滨(Gem)广泛用于胰腺癌(PACA)的化疗，但其疗效并不完全令人满意。其中一个原因是收购了Gem Residence(Gem-R)。为了阐明Gem-R的作用机制，从ASPC-1和MIA-Paca-2细胞中建立了两个Gem-R PACA细胞系。基因芯片和RT-qPCR分析表明，Gem-R PACA细胞中IL-8基因的表达显著上调。细胞因子阵列和酶联免疫吸附试验证实Gem-R细胞分泌IL-8增加。此外，我们发现，与Gem-R Paca细胞共培养显著促进了人脐静脉内皮细胞的管状形成，而抗CXCR2(IL-8的主要受体)抗体显著阻止了这一作用。我们先前报道，以IL-8/CXCR2轴为中心的趋化因子网络在PACA血管生成中起重要作用，抑制该轴具有抗肿瘤作用。由于Gem-R的获得增加了IL-8的产生，从而增加了肿瘤血管的生成，因此IL-8/CXCR2轴可能成为获得Gem-R后PACA的潜在治疗靶点。
Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem-R). To elucidate the mechanism of Gem-R, two Gem-R PaCa cell lines were established from AsPC-1 and MIA PaCa-2 cells. It was demonstrated that expression of interleukin-8 (IL-8) mRNA was significantly upregulated in Gem-R PaCa cells by cDNA microarray and RT-qPCR analyses. Increased IL-8 secretion by Gem-R cells was confirmed by cytokine array and enzyme-linked immunosorbent assay. Moreover, we found that co-culture with Gem-R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti-CXCR2 (main receptor for IL-8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL-8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem-R increased IL-8 production and consequently increased tumor angiogenesis, the IL-8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem-R.