CXCR4 is involved in CD133-induced EMT in non-small cell lung cancer
CXCR4 is involved in CD133-induced EMT in non-small cell lung cancer
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CXCR4 参与 CD133 诱导的非小细胞肺癌 EMT。
DOI：
10.3892/ijo.2016.3812
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发表时间：
2017-02-01
影响因子：
5.2
通讯作者：
Zhang, Qiuping
中科院分区：
文献类型：
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作者：
Tu, Zhenbo;Xie, Songping;Zhang, Qiuping
转移是非小细胞肺癌(NSCLC)患者死亡的主要原因，而上皮-间充质转化(EMT)是某些肿瘤转移的关键调节因子之一，因为它具有侵袭性表型。CD133是广泛应用的肿瘤干细胞(CSC)标志物，CD133阳性的癌细胞被认为是具有CSC特征的肿瘤起始细胞，而CXCR4是一种基质衍生因子-1特异性趋化因子受体，在非小细胞肺癌组织中高表达，并通过调节细胞抗凋亡参与肿瘤的进展。我们先前已经证明CXCR4通过上调细胞色素P1B1来促进NSCLC的化疗耐药，然而，CD133、CXCR4和EMT过程在NSCLC转移中的关系尚不清楚。本研究采用免疫组织化学方法检测了非小细胞肺癌组织中CD133和CXCR4的高表达，其中CD133和CXCR4与非小细胞肺癌的转移呈正相关。CD133可促进非小细胞肺癌的发生，并介导CXCR4的表达。单因素和多因素COX回归分析显示，CD133/CXCR4共表达是影响NSCLC预后的独立因素，且CD133/CXCR4共表达对EMT相关分子和转录因子的表达有调节作用。此外，我们的结果显示，在CD133+CXCR4+A549细胞中，E-钙粘蛋白和Vimentin分别同时下调和上调。而在转移性NSCLC患者中，E-钙粘蛋白表达上调，Vimentin表达下调。NSCLC患者Vimentin高表达与CD133/CXCR4共表达呈正相关，生存分析结果提示Vimentin高表达可能与NSCLC患者预后不良有关。因此，这些结果提示CD133/CXCR4/EMT轴可能是一个预后标志物，并可能为NSCLC的联合治疗提供新的靶点。
Metastasis is the major cause of death in patients with non-small cell lung cancer (NSCLC), and epithelial-mesenchymal transition (EMT) has been observed to be one of the key regulators of metastasis in certain cancers as it confers an invasive phenotype. CD133 is a widely used cancer stem cell (CSC) marker, and CD133-positive cancer cells are thought to be tumor-initiating cells with CSC characteristics, while CXCR4, a stromal-derived-factor-1 specific chemokine receptor, is highly expressed in NSCLC tissues and participates in cancer progression by regulating cell anti-apoptosis. We previously demonstrated that CXCR4 promotes NSCLC chemoresistance by upregulating CYP1B1, however, the relationship of CD133, CXCR4 and EMT processes in NSCLC metastasis are unclear. In this study, we detected a CD133 and CXCR4 high expression in tissue specimens from 64 NSCLC patients by immunohistochemistry, of which CD133 and CXCR4 were found to be positively associated with metastatic NSCLC patients. CD133 was found to promote NSCLC tumorigenesis and mediated the expression of CXCR4. Furthermore, CD133/CXCR4 co-expression was found to be an independent prognostic factor as shown by univariate and multivariate Cox regression analysis, and was observed to regulate the expression of EMT-related molecules and transcriptional factors in NSCLC. In addition, our results showed that E-cadherin and Vimentin were simultaneously downregulated and upregulated, in CD133+CXCR4+ A549 cells, respectively. While E-cadherin was upregulated and Vimentin was downregulated in metastatic NSCLC patients. Vimentin expression was also observed to have a positive correlation with CD133/CXCR4 co-expression in NSCLC patients and survival analysis results suggested that Vimentin high expression might be significantly associated with poor survival rates of the patients. Thus, these results suggest that the CD133/CXCR4/EMT axis may be a prognostic marker and may provide novel targets for combinational therapies in the treatment of NSCLC.