title: LPP inhibits collective cell migration during lung cancer dissemination.
abstract: Lipoma preferred partner (LPP) is a LIM domain protein, which has multiple functions as an actin-binding protein and a transcriptional coactivator, and it has been suggested that LPP has some roles in cell migration or invasion, however, its role in cancer cells remains to be elucidated. Here, we showed that LPP degraded N-cadherin in lung cancer, PC14PE6 cells via regulating the expression of matrix metalloproteinase 15 (MMP-15), and loss-of-LPP increases collective cell migration (CCM) and dissemination consequently. Knockdown of LPP and its functional partner, Etv5, markedly restores the full-length N-cadherin and increases cell-cell adhesion. We investigated the common target of LPP and Etv5, and found that MMP-15 is transcribed as their direct transcriptional target. Furthermore, MMP-15 could directly digest the N-cadherin extracellular domain. LPP knockdown in PC14PE6 cells increases N-cadherin-dependent CCM in the three-dimensional collagen gel invasion assays, and promoted the dissemination of cancer cells when they were orthotopically implanted in nude mice. Immunohistochemistry of lung adenocarcinoma specimens revealed the heterogeneity of LPP intensity and complementary expression of LPP and N-cadherin in the primary tumors. These findings suggest that loss-of-LPP, Etv5 or MMP-15 can be a prognostic marker of increasing malignancy.
authors.affiliation: Department of Molecular Medicine and Biochemistry, Graduate School and Faculty of Medicine, Akita University, Akita, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kuriyama
authors.affiliation: Department of Cellular and Organ pathology, Graduate School of and Faculty of Medicine, Akita University, Akita, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Division of Medical Oncology, Cancer Therapeutics Development Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yano
authors.affiliation: Department of Molecular Medicine and Biochemistry, Graduate School and Faculty of Medicine, Akita University, Akita, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Aiba
authors.affiliation: Division of Genome Biology, Group for Development of Molecular Diagnostics and Individualized Therapy, National Cancer Research Center Institute, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Department of Thorasic Surgery, Akita University, Akita, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Minamiya
authors.affiliation: Department of Cellular and Organ pathology, Graduate School of and Faculty of Medicine, Akita University, Akita, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Goto
authors.affiliation: Department of Molecular Medicine and Biochemistry, Graduate School and Faculty of Medicine, Akita University, Akita, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D053517:Matrix Metalloproteinase 15 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D060588:LIM Domain Proteins; C491227:Lpp protein, mouse; D014157:Transcription Factors; D053517:Matrix Metalloproteinase 15