title: Blockage of LMP1-modulated store-operated Ca(2+) entry reduces metastatic potential in nasopharyngeal carcinoma cell.
abstract: Epstein-Barr virus (EBV)-encoded latent membrane proteins (LMPs) expedite progression of EBV-relevant cancers. Of the full set of LMPs, latent membrane protein 1 (LMP1) was identified to uniquely augment store-operated Ca(2+) entry (SOCE). Previously, we reported that the suppression of SOCE exhibited inhibitory effects on cell migration and the extravasation from vasculature in EBV-negative nasopharyngeal carcinoma (NPC) cells. In this follow-up study, we aimed to expand our understanding of the modulation of SOCE by LMP1 and test the possibility that blockage of LMP1-modulated SOCE affects the LMP1-promoted metastatic potential. Here we showed that suppressions of the LMP1-boosted SOCE blunted the LMP1-promoted cell migration, VEGF-mediated angiogenesis and permeabilization in vitro. Blockage of SOCE inhibited vasculature-invasion of circulating cells and distant metastatic colonization in vivo. Notably, utilizing VEGFR2-EGFP-tag zebrafish we revealed that the LMP1-expressing cells arrested in a small-caliber vessel mobilized surrounding endothelial cells to facilitate vasculature-invasion. Thus, the LMP1-boosted SOCE promotes metastatic potential of NPC cells by solidifying their collaborations with the nearby non-cancer cells through the manipulation of oncogenic Ca(2+) signaling. Our study highlights the advantage of using both conventional mammal and transgenic zebrafish for developing a novel therapeutic strategy targeting the multiple steps of invasion-metastasis cascade.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan; Department of Otolaryngology-Head and Neck Oncology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning 530021, China. Electronic address: somnent@gmail.com.
authors.forename: Jiazhang
authors.initials: J
authors.lastname: Wei
authors.affiliation: Medical Photonics Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan; Department of Chemotherapy, Affiliated Cancer Hospital of Guangxi Medical University, 71 Hedi Road, Nanning 530021, China.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology-Head and Neck Oncology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning 530021, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Si
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Clark Center E150, 318 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Kanada
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Medical Photonics Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Terakawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009303:Nasopharyngeal Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015027:Zebrafish
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D002118:Calcium
keywords: Angiogenesis; Latent membrane protein 1; Metastasis; Store-operated Ca(2+) entry