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

Lampis, A. et al. (2021) MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer. Cell Death and Differentiation, 28, pp. 2970-2982. (doi: 10.1038/s41418-021-00820-0) (PMID:34226680) (PMCID:PMC8481293)

Abstract

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.

• Item Type: Articles
• Additional Information: NV was supported by Cancer Research UK (grant numbers A18052 and A26815), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (grant numbers A62, A100, A101, A159) and the European Union FP7 (grant number CIG 334261). OJS was supported by Cancer Research UK (core funding to the Beatson Institute A17196 and to his laboratory A12481 and A21139).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Horgan, Professor Paul and Braconi, Professor Chiara and Edwards, Professor Joanne and Valeri, Dr Nicola and Sansom, Professor Owen and Murgia, Dr Claudio
• Authors: Lampis, A., Hahne, J. C., Gasparini, P., Cascione, L., Hedayat, S., Vlachogiannis, G., Murgia, C., Fontana, E., Edwards, J., Horgan, P. G., Terracciano, L., Sansom, O. J., Martins, C. D., Kramer-Marek, G., Croce, C. M., Braconi, C., Fassan, M., and Valeri, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Cell Death and Differentiation
• Publisher: Springer Nature
• ISSN: 1350-9047
• ISSN (Online): 1476-5403
• Published Online: 05 July 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cell Death and Differentiation 28(1): 2970-2982
• Publisher Policy: Reproduced under a Creative Commons License