Filamin acts as a key regulator in epithelial defence against transformed cells

Mihoko Kajita; Kaoru Sugimura; Atsuko Ohoka; Jemima Burden; Hitomi Suganuma; Masaya Ikegawa; Takashi Shimada; Tetsuya Kitamura; Masanobu Shindoh; Susumu Ishikawa; Sayaka Yamamoto; Sayaka Saitoh; Yuta Yako; Ryosuke Takahashi; Takaharu Okajima; Junichi Kikuta; Yumiko Maijima; Masaru Ishii; Masazumi Tada; Yasuyuki Fujita

doi:10.1038/ncomms5428

Filamin acts as a key regulator in epithelial defence against transformed cells

Nat Commun. 2014 Jul 31:5:4428. doi: 10.1038/ncomms5428.

Authors

Mihoko Kajita¹, Kaoru Sugimura², Atsuko Ohoka¹, Jemima Burden³, Hitomi Suganuma¹, Masaya Ikegawa⁴, Takashi Shimada⁵, Tetsuya Kitamura⁶, Masanobu Shindoh⁶, Susumu Ishikawa¹, Sayaka Yamamoto¹, Sayaka Saitoh¹, Yuta Yako¹, Ryosuke Takahashi⁷, Takaharu Okajima⁷, Junichi Kikuta⁸, Yumiko Maijima⁸, Masaru Ishii⁹, Masazumi Tada¹⁰, Yasuyuki Fujita¹¹

Affiliations

¹ Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-0815, Japan.
² 1] Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan [2] JST, PRESTO, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan.
³ MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK.
⁴ Genomics, Proteomics and Biomedical Functions, Department of Life and Medical Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan.
⁵ Shimadzu Corporation, Life Science Research Center, Tokyo 101-8448, Japan.
⁶ Department of Oral Pathology and Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido 060-8586, Japan.
⁷ Graduate School of Information Science and Technology, Hokkaido University, Sapporo, Hokkaido 060-0814, Japan.
⁸ Department of Immunology and Cell Biology, Graduate School of Medicine Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
⁹ 1] Department of Immunology and Cell Biology, Graduate School of Medicine Frontier Biosciences, Osaka University, Osaka 565-0871, Japan [2] WPI-Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan [3] JST, CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan.
¹⁰ Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
¹¹ 1] Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-0815, Japan [2] MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK [3] Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.

PMID: 25079702
DOI: 10.1038/ncomms5428

Abstract

Recent studies have shown that certain types of transformed cells are extruded from an epithelial monolayer. However, it is not known whether and how neighbouring normal cells play an active role in this process. In this study, we demonstrate that filamin A and vimentin accumulate in normal cells specifically at the interface with Src- or RasV12-transformed cells. Knockdown of filamin A or vimentin in normal cells profoundly suppresses apical extrusion of the neighbouring transformed cells. In addition, we show in zebrafish embryos that filamin plays a positive role in the elimination of the transformed cells. Furthermore, the Rho/Rho kinase pathway regulates filamin accumulation and filamin acts upstream of vimentin in the apical extrusion. This is the first report demonstrating that normal epithelial cells recognize and actively eliminate neighbouring transformed cells and that filamin is a key mediator in the interaction between normal and transformed epithelial cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Death
Cell Line, Transformed
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Dogs
Embryo, Nonmammalian
Filamins / antagonists & inhibitors
Filamins / genetics*
Filamins / metabolism
Gene Expression Regulation*
Madin Darby Canine Kidney Cells
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Proto-Oncogene Proteins pp60(c-src) / genetics
Proto-Oncogene Proteins pp60(c-src) / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Transformation, Genetic
Vimentin / antagonists & inhibitors
Vimentin / genetics*
Vimentin / metabolism
Zebrafish / genetics*
Zebrafish / metabolism
rho-Associated Kinases / genetics
rho-Associated Kinases / metabolism

Substances

Filamins
RNA, Small Interfering
Vimentin
Proto-Oncogene Proteins pp60(c-src)
rho-Associated Kinases
Proto-Oncogene Proteins p21(ras)