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Lymphoma

Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma

Leukemia volume 25, pages 1598–1609 (2011)Cite this article

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Abstract

The Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), for which cytotoxic chemotherapy represents the standard of care. The high mortality associated with PEL may be explained in part by resistance of these tumors to chemotherapy. The membrane-bound glycoprotein emmprin (CD147) enhances chemoresistance in tumors through effects on transporter expression, trafficking and interactions. Interactions between hyaluronan and hyaluronan receptors on the cell surface also facilitate emmprin-mediated chemoresistance. Whether emmprin or hyaluronan-receptor interactions regulate chemotherapeutic resistance for virus-associated malignancies is unknown. Using human PEL tumor cells, we found that PEL sensitivity to chemotherapy is directly proportional to expression of emmprin, the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and a drug transporter known as the breast cancer resistance protein/ABCG2 (BCRP), and that emmprin, LYVE-1 and BCRP interact with each other and colocalize on the PEL cell surface. In addition, we found that emmprin induces chemoresistance in PEL cells through upregulation of BCRP expression, and RNA interference targeting of emmprin, LYVE-1 or BCRP enhances PEL cell apoptosis induced by chemotherapy. Finally, disruption of hyaluronan-receptor interactions using small hyaluronan oligosaccharides reduces expression of emmprin and BCRP while sensitizing PEL cells to chemotherapy. Collectively, these data support interdependent roles for emmprin, LYVE-1 and BCRP in chemotherapeutic resistance for PEL.

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Acknowledgements

We thank Dr Dean Kedes (University of Virginia, Charlottesville, VA) and Dr Dirk Dittmer (University of North Carolina, Chapel Hill, NC) for providing PEL cell lines. This work was supported by grants from the National Institutes of Health (R01-CA142362 to CP; R01-CA073839 and R01-CA082867 to BPT), the South Carolina COBRE for Oral Health (P20-RR017696; CP subproject investigator) and the MUSC Hollings Cancer Center (core Grant P30-CA138313).

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  1. Z Qin and L Dai: These authors contributed equally to this work.

  2. B P Toole and C Parsons: These authors contributed equally as senior authors.

Authors and Affiliations

  1. Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA

    Z Qin & C Parsons

  2. Department of Craniofacial Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA

    Z Qin & C Parsons

  3. Department of Regenerative Medicine and Cell Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA

    L Dai, M Bratoeva, M G Slomiany & B P Toole

  4. Key Laboratory of Arrhythmias, Ministry of Education, China (East Hospital, Tongji University School of Medicine), Shanghai, China

    Z Qin & L Dai

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Qin, Z., Dai, L., Bratoeva, M. et al. Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma. Leukemia 25, 1598–1609 (2011). https://doi.org/10.1038/leu.2011.144

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