title: Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma.
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.
authors.affiliation: Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Qin
authors.forename: L
authors.initials: L
authors.lastname: Dai
authors.forename: M
authors.initials: M
authors.lastname: Bratoeva
authors.forename: M G
authors.initials: MG
authors.lastname: Slomiany
authors.forename: B P
authors.initials: BP
authors.lastname: Toole
authors.forename: C
authors.initials: C
authors.lastname: Parsons
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D051926:Basigin / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000503:physiopathology; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D033921:Vesicular Transport Proteins / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C497886:BSG protein, human; D017931:DNA Primers; C119248:LYVE1 protein, human; D033921:Vesicular Transport Proteins; D051926:Basigin