∆133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling.
∆133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling.
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Δ133P53同工型通过白介素6激活Jak-Stat和Rhoa-Rock信号传导促进肿瘤侵袭和转移。
DOI：
10.1038/s41467-017-02408-0
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发表时间：
2018-01-17
影响因子：
16.6
通讯作者：
Braithwaite AW
中科院分区：
文献类型：
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作者：
Campbell H;Fleming N;Roth I;Mehta S;Wiles A;Williams G;Vennin C;Arsic N;Parkin A;Pajic M;Munro F;McNoe L;Black M;McCall J;Slatter TL;Timpson P;Reddel R;Roux P;Print C;Baird MA;Braithwaite AW
∆122P53小鼠(∆133P53亚型的模型)容易肿瘤，有广泛的炎症和血清IL-6升高。为了研究IL-6的作用，我们将∆122p53小鼠与IL-6缺失的小鼠杂交。在这里，我们表明，IL-6的丢失减少了JAK-STAT信号，肿瘤的发病率和转移。我们还表明，JAK122p53激活RhoA-ROCK信号导致肿瘤细胞侵袭，这是IL-6依赖的，可以通过抑制∆-STAT和RhoA-ROCK通路来减少。类似地，我们发现Δ133p53激活了这些通路，导致了结直肠癌细胞的侵袭和迁移表型。大肠肿瘤的基因表达分析显示，∆133TP53mRNA相关的GPCR信号丰富。∆133TP53mRNA水平升高的患者无病生存期较短。我们的结果表明，∆133p53通过激活JAK-STAT和RhoA-ROCK通路促进肿瘤侵袭，其肿瘤具有高∆133TP53的患者可能受益于针对这些通路的治疗。Δ133P53亚型的异常表达与许多癌症有关。在这里，作者利用了一个容易发生肿瘤和炎症的Δ133P53亚型的模型，表明Δ133P53通过激活JAK-STAT和RhoA-ROCK通路以IL-6依赖的方式促进肿瘤细胞的侵袭。
∆122p53 mice (a model of ∆133p53 isoform) are tumour-prone, have extensive inflammation and elevated serum IL-6. To investigate the role of IL-6 we crossed ∆122p53 mice with IL-6 null mice. Here we show that loss of IL-6 reduced JAK-STAT signalling, tumour incidence and metastasis. We also show that ∆122p53 activates RhoA-ROCK signalling leading to tumour cell invasion, which is IL-6-dependent and can be reduced by inhibition of JAK-STAT and RhoA-ROCK pathways. Similarly, we show that Δ133p53 activates these pathways, resulting in invasive and migratory phenotypes in colorectal cancer cells. Gene expression analysis of colorectal tumours showed enrichment of GPCR signalling associated with ∆133TP53 mRNA. Patients with elevated ∆133TP53 mRNA levels had a shorter disease-free survival. Our results suggest that ∆133p53 promotes tumour invasion by activation of the JAK-STAT and RhoA-ROCK pathways, and that patients whose tumours have high ∆133TP53 may benefit from therapies targeting these pathways. Aberrant expression of the Δ133p53 isoform is linked to many cancers. Here, the authors utilise a model of the Δ133p53 isoform that is prone to tumours and inflammation, showing that Δ133p53 promotes tumour cell invasion by activation of the JAK-STAT and RhoA-ROCK pathways in an IL-6 dependent manner.
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DOI：
10.1084/jem.20130783
发表时间：
2013-09-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iannello A;Thompson TW;Ardolino M;Lowe SW;Raulet DH
通讯作者：
Raulet DH
影响因子：
11.2
作者：
Lowe JM;Menendez D;Bushel PR;Shatz M;Kirk EL;Troester MA;Garantziotis S;Fessler MB;Resnick MA
通讯作者：
Resnick MA
影响因子：
11
作者：
Huang, SP;Wu, MS;Lin, JT
通讯作者：
Lin, JT
影响因子：
10.3
作者：
Cortez, Maria Angelica;Ivan, Cristina;Welsh, James W.
通讯作者：
Welsh, James W.
影响因子：
3
作者：
Klampfer L
通讯作者：
Klampfer L