title: CXCR4 is involved in CD133-induced EMT in non-small cell lung cancer.
abstract: 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.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Songping
authors.initials: S
authors.lastname: Xie
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xiong
authors.affiliation: School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Yinchu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Engineering and Technology College, Hubei University of Technology, Wuhan, Hubei, P.R. China.
authors.forename: Xiangyong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Kingsley Miyanda
authors.initials: KM
authors.lastname: Tembo
authors.affiliation: Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Thoracic Oncology, Zhongnan Hospital, Wuhan, Hubei, P.R. China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Pan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Ehtisham
authors.initials: E
authors.lastname: Altaf
authors.affiliation: Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Ganjun
authors.initials: G
authors.lastname: Kang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, P.R. China.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000473:pathology*; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; C000606023:PROM1 protein, human; D019718:Receptors, CXCR4