- Title
- MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer
- Creator
- Lampis, Andrea; Hahne, Jens C.; Terracciano, Luigi; Sansom, Owen J.; Martins, Carlos D.; Kramer-Marek, Gabriela; Croce, Carlo M.; Braconi, Chiara; Fassan, Matteo; Valeri, Nicola; Gasparini, Pierluigi; Cascione, Luciano; Hedayat, Somaieh; Vlachogiannis, Georgios; Murgia, Caludio; Fontana, Eelsa; Edwards, Joanna; Horgan, Paul G.
- Relation
- Cell Death and Differentiation Vol. 28, p. 2970-2982
- Publisher Link
- http://dx.doi.org/10.1038/s41418-021-00820-0
- Publisher
- Springer
- Resource Type
- journal article
- Date
- 2021
- Description
- 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.
- Subject
- Junctional adhesion molecules (JAMs); cell; colorectal cancer; metastasis; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1476475
- Identifier
- uon:49830
- Identifier
- ISSN:1350-9047
- Rights
- Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Language
- eng
- Full Text
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