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.

Overview of Cancer Stem Cells and Stemness for Community Oncologists

“…As in ovarian cancer, CSCs expressing both CXCR4 and CD133 exhibited the greatest tumor-initiating potential, resistance to cisplatin, and overexpression of the ABCG2 drug efflux pump compared with CD133 − /CXCR4 + and CD133 + /CXCR4 − CSCs, as well as CD133 −/ CXCR4 − cells [89]. Similar phenomenon was reported in other cancers as well [90]. The transformation of CSCs into mesenchymal invasive phenotypes has been shown to be mediated by stemness pathways.…”

Docetaxel promotes cell apoptosis and decreases SOX2 expression in CD133‑expressing hepatocellular carcinoma stem cells by suppressing the PI3K/AKT signaling pathway

“…CD133, also known as prominin-1, was first identified as a potential subpopulation of cancer stem cells (4,5). It is now widely described as a marker of cancer stem cells in the brain (6), esophagus (7), lung (8), colon (9), prostate (10) and ovaries (11). Notably, CD133 is also a marker highly recognized in HCC stem cells (12), which is reported to be an important target for improving chemotherapeutic efficacy of recurrent HCC cells (13).…”

miR-181b-5p mediates TGF-β1-induced epithelial-to-mesenchymal transition in non-small cell lung cancer stem-like cells derived from lung adenocarcinoma A549 cells

“…EMT plays a key role in the metastasis of NSCLC (16). Cancer cells treated with TGF-β1, an inducer of EMT, show decreased expression of E-cadherin and increased expression of vimentin, N-cadherin and matrix metalloproteinases (MMP), such as MMP-2, MMP-3 and MMP-9.…”