Association of Cytoplasmic CXCR4 With Loss of Epithelial Marker and Activation of ERK1/2 and AKT Signaling Pathways in Non–Small-Cell Lung Cancer

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Identification of activated CXC-chemokine receptor 4 (CXCR4) in tumor biopsies would assist in selecting patients for potential CXCR4-targeted therapy. We analyzed 94 non–small-cell lung cancer (NSCLC) tissues by IHC of CXCR4 and its downstream signaling proteins as well as a mesenchymal transition (EMT) marker. We found that sub-cellular localization of CXCR4 was associated with its downstream signals and cytoplasmic CXCR4 correlated with EMT markers in NSCLC.


Compelling evidence demonstrates that CXC-chemokine receptor 4 (CXCR4) is involved in tumor invasion, angiogenesis, metastasis, and resistance to chemotherapy in addition to being one of the coreceptors for T-tropic human immunodeficiency virus entry into T cells. However, it remains controversial as to how to identify functionally activated CXCR4 in tumor biopsies, which would assist in determining which patients may benefit from potential CXCR4-targeted therapy.

Materials and Methods:

Immunohistochemistry (IHC) staining on archival tissues of patients with non–small-cell lung cancer (NSCLC) was used to detect a panel of biomarkers, including phospho-ERK1/2, phospho-AKT, and E-cadherin, which are relevant to downstream signaling of CXCR4 and epithelial to mesenchymal transition (EMT). We also examined whether subcellular localization of CXCR4 could help define possible activation of CXCR4.


A total of 94 primary tumor tissue samples from patients with NSCLC were included. Sixty-six patients had both cytomembranous and nuclear staining of CXCR4, 22 had solely nuclear staining, 5 had solely cytomembranous staining, and 1 had negative staining. Cytoplasmic location of CXCR4 with or without nuclear location was associated with loss of the epithelial marker E-cadherin (P = .0015) and activation of ERK1/2 (P = .0121) and AKT (P = .0024), suggesting EMT in these tumors; whereas tumors with only nuclear location of CXCR4 were more indolent and preserved an epithelial phenotype.


Our study suggests that different subcellular localization of CXCR4 may be associated with different activation states; cytoplasmic CXCR4 seems to correlate with biomarker changes associated with EMT in NSCLC.

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