MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer.
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Date
2021-07-05ICR Author
Author
Lampis, A
Hahne, JC
Gasparini, P
Cascione, L
Hedayat, S
Vlachogiannis, G
Murgia, C
Fontana, E
Edwards, J
Horgan, PG
Terracciano, L
Sansom, OJ
Martins, CD
Kramer-Marek, G
Croce, CM
Braconi, C
Fassan, M
Valeri, N
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Research team
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics
Language
eng
Date accepted
2021-06-09
License start date
2021-07-05
Citation
Cell death and differentiation, 2021
Publisher
SPRINGERNATURE