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MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2021-07-05 , DOI: 10.1038/s41418-021-00820-0
Andrea Lampis 1 , Jens C Hahne 1 , Pierluigi Gasparini 2, 3, 4 , Luciano Cascione 5, 6 , Somaieh Hedayat 1 , Georgios Vlachogiannis 1 , Claudio Murgia 7 , Elisa Fontana 1 , Joanne Edwards 8 , Paul G Horgan 8 , Luigi Terracciano 9, 10 , Owen J Sansom 7, 8 , Carlos D Martins 11 , Gabriela Kramer-Marek 11 , Carlo M Croce 2 , Chiara Braconi 8 , Matteo Fassan 10, 12, 13 , Nicola Valeri 1, 14, 15
Affiliation  

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.



中文翻译:

MIR21诱导的连接粘附分子A丢失促进结直肠癌致癌途径、进展和转移的激活

连接粘附分子 (JAM) 在细胞通透性、极性和迁移中起关键作用。JAM-A 是 JAM 家族的一种关键蛋白质,在包括癌症在内的许多情况下都会发生改变;然而,JAM-A 失调对致癌作用的影响似乎是组织依赖性和器官依赖性的,这对使用 JAM-A 作为生物标志物或治疗靶点具有重要意义。在这里,我们测试了 JAM-A 下调在原发性和转移性结直肠癌 (CRC) ( n  = 947) 中的表达和预后作用。我们表明,在约 60% 的 CRC 中观察到 JAM-A 下调,并且与四组 II 期和 III 期 CRC 的不良结果相关(n = 1098)。在细胞系单层、3D 球体、患者衍生的类器官和异种移植中使用 JAM-A 敲低、重新表达和拯救实验,我们证明 JAM-A 沉默促进 2D 和 3D 细胞模型中的增殖和迁移,并增加肿瘤体积和转移体内。使用基因表达和蛋白质组学分析,我们表明 JAM-A 下调导致 ERK、AKT 和 ROCK 通路的激活,并导致骨形态发生蛋白 7 表达降低。我们确定 MIR21 上调是 JAM-A 下调的原因,并表明 JAM-A 拯救减轻了 MIR21 过表达对癌症表型的影响。我们的研究结果确定了一个新的分子环,涉及 MIR21 失调、JAM-A 沉默和多种致癌途径的激活,以促进 CRC 的侵袭性和转移。

更新日期:2021-07-05
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