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CXC Chemokine Receptor 4 Expression and Function in Human Anaplastic Thyroid Cancer Cells

Laboratory of Endocrine Cell Biology (Ju.H.H., Ji.H.H., H.K.C., D.W.K., E.S.H., J.M.S., H.K., O.-Y.K., H.K.R., D.Y.J., M.S.), National Research Laboratory Program, Department of Internal Medicine, Chungnam National University College of Medicine; and Department of Biology (K.-H.Y.), College of Natural Sciences, Chungnam National University, Daejeon 301-721, Korea

Address all correspondence and requests for reprints to: Minho Shong and Deog Yeon Jo, Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University College of Medicine, 640 Daesadong Chungku Daejeon, Taejon 301-721, Korea. E-mail: minhos{at}cnu.ac.kr.

Anaplastic thyroid carcinomas (ATCs) are highly aggressive, extremely lethal human cancers with poor therapeutic response. Chemokines are a superfamily of small cytokine-like proteins that induce, through their interaction with G protein-coupled receptors, cytoskeletal rearrangement, firm adhesion to endothelial cells, and directional migration. In this study, we characterized the expression of CXC chemokine receptor 4 (CXCR4) and analyzed its functions in ARO cells, a human ATC cell. The normal primary cultured thyroid cells and ATC cell lines expressed CXCR4 and stromal cell-derived factor (SDF)-1 transcripts, detected by RT-PCR. Fluorescence activated cell sorting analysis of CXCR4 expression in normal and ATC cells showed that ARO cells expressed significant levels of CXCR4. FRO, NPA, and normal thyroid cells did not express membrane CXCR4, as determined by fluorescence activated cell sorting analysis. To identify the functional role of CXCR4 in ARO cells, we treated ARO cells with SDF-1 and analyzed the signaling pathways, cellular migration, and proliferation. SDF-1 enhanced the migration but did not affect the proliferation of ARO cells or activate the Janus kinase/signal transducer and activator of transcription signaling pathways. However, SDF-1/CXCR4 activation resulted in phosphorylation of the p70S6 kinase and its target protein, ribosomal S6 protein, and also activation of the ERK1/ERK2 signaling pathways. Furthermore, SDF-1/CXCR4- mediated activation of the p70S6 kinase and phosphorylation of the S6 protein were inhibited by treatment with an mTOR/FRAP inhibitor.

The specificity of the CXCR4-mediated migration of ARO cells was demonstrated by the dose-dependent inhibition of migration by neutralizing anti-CXCR4. The ATC cells, FRO and NPA, which do not express CXCR4, did not demonstrate significant SDF-1-mediated migration in vitro. In addition, the CXCR4-mediated migration of ARO cells was inhibited by treatment with pertussis toxin (a Gi-protein inhibitor) and PD 98059 (a mitogen-activated ERK kinase inhibitor) but not by LY294002 and wortmanin, phosphatidylinositol 3-kinase inhibitors.

These findings suggest that a subset of ATC cells expresses functional CXCR4, which may be important in tumor cell migration and local tumor invasion.

This work was supported by the National Research Laboratory Program (M1-0104-00-0014), Ministry of Science and Technology, Seoul, Korea.

Abbreviations: ATC, Anaplastic thyroid cancer; CXCR4, CXC chemokine receptor 4; FBS, fetal bovine serum; IB, inhibitor B; HA, hemagglutinin antigen; JAK, Janus kinase; MTT, methylthiazoletetrazolium; NF-B, nuclear factor-B; PBSF, pre-B-cell growth-stimulating factor; PI3K, phosphatidylinositol 3-kinase; PTX, pertussis toxin; rh, recombinant human; SDF, stromal cell derived factor; STAT, signal transducer and activator of transcription.

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