title: Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration.
abstract: BACKGROUND
  Cell migration is a critical determinant of cancer metastasis, and a better understanding of the genes involved will lead to the identification of novel targets aimed at preventing cancer dissemination. KIAA1199 has been shown to be upregulated in human cancers, yet its role in cancer progression was hitherto unknown.
  
  
  METHODS
  Clinical relevance was assessed by examining KIAA1199 expression in human cancer specimens. In vitro and in vivo studies were employed to determine the function of KIAA1199 in cancer progression. Cellular localization of KIAA1199 was microscopically determined. SNAP-tag pull-down assays were used to identify binding partner(s) of KIAA1199. Calcium levels were evaluated using spectrofluorometric and fluorescence resonance energy transfer analyses. Signaling pathways were dissected by Western blotting. Student t test was used to assess differences. All statistical tests were two-sided.
  
  
  RESULTS
  KIAA1199 was upregulated in invasive breast cancer specimens and inversely associated with patient survival rate. Silencing of KIAA1199 in MDA-MB-435 cancer cells resulted in a mesenchymal-to-epithelial transition that reduced cell migratory ability in vitro (75% reduction; P < .001) and decreased metastasis in vivo (80% reduction; P < .001). Gain-of-function assays further demonstrated the role of KIAA1199 in cell migration. KIAA1199-enhanced cell migration required endoplasmic reticulum (ER) localization, where it forms a stable complex with the chaperone binding immunoglobulin protein (BiP). A novel ER-retention motif within KIAA1199 that is required for its ER localization, BiP interaction, and enhanced cell migration was identified. Mechanistically, KIAA1199 was found to mediate ER calcium leakage, and the resultant increase in cytosolic calcium ultimately led to protein kinase C alpha activation and cell migration.
  
  
  CONCLUSIONS
  KIAA1199 serves as a novel cell migration-promoting gene and plays a critical role in maintaining cancer mesenchymal status.
authors.affiliation: Affiliations of authors: Department of Medicine/Cancer Prevention (NAE, CK, H-LN, KZ, AD, AP-G, JC), Department of Pathology (YH, JC), Department of Medicine/Hematology & Oncology (WFB, SZ), Stony Brook University, Stony Brook, NY; Department of Research, Veterans Affair Medical Center, Northport, NY (H-LN, PK, SZ); Centre for Blood Research and Departments of Biochemistry and Molecular Biology and Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada (AD).
authors.forename: Nikki A
authors.initials: NA
authors.lastname: Evensen
authors.forename: Cem
authors.initials: C
authors.lastname: Kuscu
authors.forename: Hoang-Lan
authors.initials: HL
authors.lastname: Nguyen
authors.forename: Kevin
authors.initials: K
authors.lastname: Zarrabi
authors.forename: Antoine
authors.initials: A
authors.lastname: Dufour
authors.forename: Pournima
authors.initials: P
authors.lastname: Kadam
authors.forename: You-Jun
authors.initials: YJ
authors.lastname: Hu
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Pulkoski-Gross
authors.forename: Wadie F
authors.initials: WF
authors.lastname: Bahou
authors.forename: Stanley
authors.initials: S
authors.lastname: Zucker
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D036681:Fluorescence Recovery After Photobleaching; D031541:Fluorescence Resonance Energy Transfer; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D006821:Hyaluronoglucosaminidase; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence; D015854:Up-Regulation
chemical_list: D011506:Proteins; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; C491433:CEMIP protein, human; D006821:Hyaluronoglucosaminidase; D002118:Calcium