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Authors Wang M, Lin T, Wang YC, Gao S, Yang ZY, Hong X, Chen GY
Received 23 January 2017
Accepted for publication 19 May 2017
Published 29 June 2017 Volume 2017:10 Pages 3215—3224
DOI https://doi.org/10.2147/OTT.S133055
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Geoffrey Pietersz
Aims: Poor
efficacy of chemotherapy drugs in non-small-cell lung cancer (NSCLC) is the key
reason for the failure of treatment, but the mechanism of this remains largely
unknown. Stromal cell-derived factor 1-alpha (SDF-1α/CXCL12) is a small
chemotactic cytokine protein that plays an important role in tumor progression.
In this study, we investigated the anti-apoptotic mechanism of the CXCL12/CXCR4
axis in response to cisplatin, a commonly used chemotherapeutic drug, in human
lung adenocarcinoma A549 cells.
Methods: CXCL12 blocks cisplatin-induced apoptosis in A549, and the results were
shown by propidium iodide/annexin V staining in vitro. The mechanism of CXCL12
stimulating phosphorylation of STAT3 through CXCR4/JAK2 was demonstrated by
immunofluorescence and Western blotting. The expression of CXCL12 and p-STAT3
in clinical specimens was examined by immunohistochemistry.
Results: CXCL12 significantly decreased the ratio of apoptotic cells and
stimulation of phospho-signal transducer and activator of transcription
(p-STAT)-3 in a time-dependent manner through interaction with CXCR4. Among the
signaling molecules downstream of CXCR4, the JAK2/STAT3 pathway plays a
predominant role in the anti-apoptotic effect of CXCL12. Analysis of clinical specimens
revealed that increased CXCL12 and p-STAT3 expression correlates with enhanced
lung cancer progression.
Conclusion: These data suggest that CXCR4 contributes to CXCL12-mediated
anti-apoptosis by activating JAK2/STAT3 pathway in NSCLC cells. Therefore,
targeting CXCL12/CXCR4 signaling pathway reveals a potential therapeutic
approach for NSCLC.
Keywords: CXCL12, CXCR4, JAK2/STAT3, apoptosis, non-small-cell lung cancer