title: TRIM27/MRTF-B-dependent integrin β1 expression defines leading cells in cancer cell collectives.
abstract: For collective invasion, cancer cells form cohesive groups comprised of leading cells (LCs) at the forefront and following cells (FCs) at the rear. However, the molecular mechanisms that define LCs and FCs remain elusive. Here, we demonstrated that LCs, but not FCs, upregulated the expression of integrin β1 after the loss of intercellular adhesion. The LC-specific expression of integrin β1 was posttranscriptionally regulated by the TRIM27/MRTF-B complex in response to the loss of intercellular adhesion, thereby regulating the stability and translation of integrin β1 mRNA via microRNA-124 in LCs. Accordingly, depletion of TRIM27 and MRTF-B abrogated the upregulation of integrin β1 in LCs and blocked the invasion of cancer cell groups in vitro and in vivo. Therefore, our findings revealed that the specific function of LCs was defined by intrinsic mechanisms related to the presence of the cell's free surface, providing insights into the regulation of intratumor heterogeneity.
authors.affiliation: Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.affiliation: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Transdisciplinary Life Science Course, Faculty of Advanced Life Science, Hokkaido University, N10-W8, Kita-ku, Sapporo 060-0810, Japan; Research Center for Cooperative Projects, Graduate School of Medicine, Hokkaido University, N15-W7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Haga
authors.affiliation: Transdisciplinary Life Science Course, Faculty of Advanced Life Science, Hokkaido University, N10-W8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Sumire
authors.initials: S
authors.lastname: Ishida
authors.affiliation: Department of Biochemistry II, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Biochemistry II, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Shimane University, 89-1 Izumo, Shimane 693-8501, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Urano
authors.affiliation: Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Mii
authors.affiliation: Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Liang
authors.initials: L
authors.lastname: Weng
authors.affiliation: Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Ishida-Takagishi
authors.affiliation: Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Asai
authors.affiliation: Division of Molecular Pathology, Center for Neurological Disease and Cancer, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Asai
authors.affiliation: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Department of Pathology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0374, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakumo
authors.affiliation: Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: mtakaha@med.nagoya-u.ac.jp.
authors.forename: Masahide
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D000070584:Tripartite Motif Proteins
chemical_list: D004268:DNA-Binding Proteins; D019012:Integrin beta1; D009687:Nuclear Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C064419:TRIM27 protein, human; D000070584:Tripartite Motif Proteins; C503315:myocardin-related transcription factor B, mouse; C489296:Trim27 protein, mouse