MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer.

Autor: Lampis A; Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Hahne JC; Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Gasparini P; Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.; School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia., Cascione L; Bioinformatics Core Unit, Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland.; Swiss Institute of Bioinformatics, Bellinzona, Switzerland., Hedayat S; Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Vlachogiannis G; Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Murgia C; Cancer Research UK Beatson Institute, Glasgow, UK., Fontana E; Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Edwards J; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Horgan PG; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Terracciano L; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; IRCCS Humanitas Research Hospital, Milan, Italy., Sansom OJ; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Martins CD; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK., Kramer-Marek G; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK., Croce CM; Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA., Braconi C; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Fassan M; IRCCS Humanitas Research Hospital, Milan, Italy.; Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, Italy.; Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy., Valeri N; Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK. nicola.valeri@icr.ac.uk.; Department of Medicine, The Royal Marsden Hospital, London, UK. nicola.valeri@icr.ac.uk.; Division of Surgery and Cancer, Imperial College London, London, UK. nicola.valeri@icr.ac.uk.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2021 Oct; Vol. 28 (10), pp. 2970-2982. Date of Electronic Publication: 2021 Jul 05.
DOI: 10.1038/s41418-021-00820-0
Abstrakt: Junctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.
(© 2021. The Author(s).)
Databáze: MEDLINE
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