Versican upregulation in Sézary cells alters growth, motility and resistance to chemotherapy.
Sézary syndrome (SéS) represents a leukemic variant of cutaneous T-cell lymphoma, whose etiology is still unknown. To identify dyregulated genes in SéS, we performed transcriptional profiling of Sézary cells (SCs) obtained from peripheral blood of patients with SéS. We identified versican as the highest upregulated gene in SCs. VCAN is an extracellular matrix proteoglycan, which is known to interfere with different cellular processes in cancer. Versican isoform V1 was the most commonly upregulated isoform in SCs. Using a lentiviral plasmid, we overexpressed versican V1 isoform in lymphoid cell lines, which altered their growth behavior by promoting formation of smaller cell clusters and by increasing their migratory capacity towards stromal cell-derived factor 1, thus promoting skin homing. Versican V1 overexpression exerted an inhibitory effect on cell proliferation, partially by promoting activation-induced cell death. Furthermore, V1 overexpression in lymphoid cell lines increased their sensitivity to doxorubicin and gemcitabine. In conclusion, we confirm versican as one of the dysregulated genes in SéS and describe its effects on the biology of SCs. Although versican overexpression confers lymphoid cells with increased migratory capacity, it also makes them more sensitive to activation-induced cell death and some chemotherapeutics, which could be exploited further for therapeutic purposes.
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
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K
Fujii
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
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MB
Karpova
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
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K
Asagoe
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
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O
Georgiev
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
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Dummer
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
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Urosevic-Maiwald
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012751:Sezary Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured; D053675:Versicans / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C508322:VCAN protein, human; D053675:Versicans