CXCR4 promotes cisplatin-resistance of non-small cell lung cancer in a CYP1B1-dependent manner.
CXCR4 promotes cisplatin-resistance of non-small cell lung cancer in a CYP1B1-dependent manner.
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DOI：
10.3892/or.2016.5289
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发表时间：
2017-02
期刊：
影响因子：
4.2
通讯作者：
S. Xie;Zhenbo Tu;J. Xiong;Gan-jun Kang;Lina Zhao;Weidong Hu;Haiyan Tan;K. Tembo;Qianshan Ding;Xinzhou Deng;Jie Huang;Qiuping Zhang
中科院分区：
文献类型：
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作者：
S. Xie;Zhenbo Tu;J. Xiong;Gan-jun Kang;Lina Zhao;Weidong Hu;Haiyan Tan;K. Tembo;Qianshan Ding;Xinzhou Deng;Jie Huang;Qiuping Zhang
化疗耐药是导致晚期肺癌治疗失败和高死亡率的主要原因。顺铂是一种重要的肺癌化疗药物，但由于化疗耐药性的产生，其化疗效果大大降低。CXCR 4是一种基质衍生因子-1特异性趋化因子受体，在非小细胞肺癌（NSCLC）组织中高度表达，并通过调节细胞生长、凋亡或侵袭参与癌症进展。因此，在本研究中，我们研究了CXCR 4是否在NSCLC的顺铂相关耐药中发挥作用。采用免疫组化法检测64例NSCLC组织中CXCR 4的表达。本研究采用顺铂耐药的非小细胞肺癌细胞A549/DDP及其亲本细胞A549。进行RNA干扰以沉默CXCR 4。探讨CXCR 4对NSCLC细胞耐药性、凋亡和生长的影响，以及与细胞色素P450相关分子CYP 1B 1表达的关系。最后，我们发现CXCR 4在顺铂耐药的NSCLC患者和A549/DDP细胞系中显著高表达。通过siRNA抑制CXCR 4逆转了化疗耐药性并降低了肿瘤细胞增殖。生物信息学分析表明，CYP 1B 1与CXCR 4的表达呈正相关，CYP 1B 1沉默可显著降低CXCR 4的表达水平和顺铂耐药性。免疫组化也证实了CYP 1B 1在顺铂耐药患者的NSCLC组织中上调。总之，我们的研究结果表明，CXCR 4在NSCLC中的过度表达通过CXCR 4介导的CYP 1B 1上调促进顺铂耐药。因此，它可以被用作NSCLC化疗耐药患者的潜在治疗靶点，并用作顺铂反应的临床预测因子。
Chemoresistance is the main cause of treatment failure and high mortality in advanced lung cancer. Cisplatin, an important chemotherapeutic agent for lung cancer, has been observed to show enormously reduced chemotherapeutic efficacy owing to the development of chemoresistance. CXCR4, a stromal-derived-factor-1 specific chemokine receptor, is highly expressed in non-small cell lung cancer (NSCLC) tissues and participates in cancer progression by regulating cell growth, apoptosis or invasion. In this study, we therefore investigated whether CXCR4 plays a role in the cisplatin associated resistance in NSCLC. We detected the expression of CXCR4 in tissue specimens from 64 NSCLC patients by immunohistochemistry. Cisplatin-resistant NSCLC cells A549/DDP and its parental A549 cells were employed in this study. RNA interference was performed to silence the CXCR4. The influence of CXCR4 on tumor cell chemoresistance, apoptosis and growth, as well as the relationship between CXCR4 and the expression of cytochrome p450 associated molecule CYP1B1 in NSCLC were evaluated. Finally, we found CXCR4 was significantly highly expressed in cisplatin-resistant NSCLC patients and the A549/DDP cell line. CXCR4 inhibition by siRNA reversed chemoresistance and decreased tumor cell proliferation. Bioinformatics analysis showed that the expression of CYP1B1 had a positive correlation with CXCR4, the CYP1B1 silencing significantly decreased CXCR4 expression levels and cisplatin resistance. Immunohistochemistry also verified that CYP1B1 was upregulated in NSCLC tissues of cisplatin-resistant patients. In conclusion, our results indicate that overexpression of CXCR4 in NSCLC promotes cisplatin resistance via CXCR4-mediated CYP1B1 upregulation. Thus, it can be used as a potential therapeutic target in NSCLC chemoresistance patients and be used as a clinical predictor of cisplatin response.