Ppp6c deficiency accelerates K-ras(G12D) -induced tongue carcinogenesis.
Ppp6c deficiency accelerates K-ras(G12D) -induced tongue carcinogenesis.
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DOI：
10.1002/cam4.3962
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发表时间：
2021-07
期刊：
影响因子：
4
通讯作者：
Shima H
中科院分区：
文献类型：
--
作者：
Kishimoto K;Kanazawa K;Nomura M;Tanaka T;Shigemoto-Kuroda T;Fukui K;Miura K;Kurosawa K;Kawai M;Kato H;Terasaki K;Sakamoto Y;Yamashita Y;Sato I;Tanuma N;Tamai K;Kitabayashi I;Matsuura K;Watanabe T;Yasuda J;Tsuji H;Shima H
对携带突变RAS的癌症缺乏有效的治疗方法。在果蝇中，有报道PP6抑制突变的RAS的致瘤性。然而，PP6如何在哺乳动物中调控致癌RAS的信息有限。我们研究了PP6基因(Ppp6c)缺陷对K(K-RasG12D)和KP(K-RasG12D+Trp53缺陷)诱导的小鼠舌癌发生的影响。K型和Kp型小鼠在Ppp6c缺乏症诱导后约2周出现舌原位鳞状细胞癌，并因体重减轻20%而被安乐死。转录组分析显示，Ppp6c缺陷型舌组织与野生型Ppp6c舌组织的基因表达存在显著差异，而Trp53缺陷型的影响相对较小。然后，我们分析了Ppp6c缺乏通常改变的基因，有或没有TrP53缺乏，并确定了一组集中在KEGG数据库中的通路，定义为“癌症通路”和“细胞因子-细胞因子受体相互作用”。然后我们评估了致癌RAS下游的信号和受PP6底物调控的信号，发现在K-RasG12D存在的情况下，Ppp6c的缺失增强了ERK-ELK1-FOS、AKT-4EBP1和AKT-FOXO-CylinD1轴的激活。Ppp6c缺失联合K-RasG12D还可增加DNA双链断裂，激活NF-κB信号，上调IL-1β、COX2和肿瘤坏死因子。在这里，我们研究了PP6基因(Ppp6c)缺陷对K(K-RasG12D)-和KP(K-RasG12D)+Trp53缺陷诱导的小鼠舌癌发生的影响。在Ppp6c缺乏诱导的大约2周后，K和Kp基因型的小鼠出现舌部原位鳞状细胞癌。在K-RasG12D存在的情况下，Ppp6c的缺失增强了ERK-ELK1-FOS、AKT-4EBP1和AKT-FOXO-CylinD1轴的激活。Ppp6c缺失与K-RasG12D结合也激活了NFkB信号，上调了导致细胞因子爆炸的肿瘤坏死因子。我们发现PP6通过抑制ERK、AKT和NFkB的活性而发挥肿瘤抑制作用。
Effective treatments for cancer harboring mutant RAS are lacking. In Drosophila, it was reported that PP6 suppresses tumorigenicity of mutant RAS. However, the information how PP6 regulates oncogenic RAS in mammals is limited. We examined the effects of PP6 gene (Ppp6c) deficiency on tongue tumor development in K (K‐rasG12D)‐ and KP (K‐rasG12D + Trp53‐deficient)‐inducible mice. Mice of K and KP genotypes developed squamous cell carcinoma in situ in the tongue approximately 2 weeks after the induction of Ppp6c deficiency and was euthanized due to 20% loss of body weight. Transcriptome analysis revealed significantly different gene expressions between tissues of Ppp6c‐deficient tongues and those of Ppp6c wild type, while Trp53 deficiency had a relatively smaller effect. We then analyzed genes commonly altered by Ppp6c deficiency, with or without Trp53 deficiency, and identified a group concentrated in KEGG database pathways defined as ‘Pathways in Cancer’ and ‘Cytokine‐cytokine receptor interaction’. We then evaluated signals downstream of oncogenic RAS and those regulated by PP6 substrates and found that in the presence of K‐rasG12D, Ppp6c deletion enhanced the activation of the ERK‐ELK1‐FOS, AKT‐4EBP1, and AKT‐FOXO‐CyclinD1 axes. Ppp6c deletion combined with K‐rasG12D also enhanced DNA double‐strand break (DSB) accumulation and activated NFκB signaling, upregulating IL‐1β, COX2, and TNF. Here, we examined the effects of PP6 gene (Ppp6c) deficiency on tongue tumor development in K (K‐rasG12D)‐ and KP (K‐rasG12D + Trp53‐deficient)‐inducible mice. Mice of K and KP genotypes developed squamous cell carcinoma in situ in the tongue approximately 2 weeks after the induction of Ppp6c deficiency. Ppp6c deletion in the presence of K‐rasG12D enhanced the activation of the ERK‐Elk1‐FOS, AKT‐4EBP1, and AKT‐FOXO‐CyclinD1 axes. Ppp6c deletion combined with K‐rasG12D also activated NFkB signaling, upregulating TNF which leads to an explosion of cytokines. We found that PP6 functions as a tumor suppressor by suppressing the activity of ERK, AKT, and NFkB.
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影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
8.8
作者：
Ma X;Lu JY;Dong Y;Li D;Malagon JN;Xu T
通讯作者：
Xu T
影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A
影响因子：
5.4
作者：
Wu, Nannan;Liu, Xuyuan;Tang, Hua
通讯作者：
Tang, Hua
影响因子：
4.7
作者：
Suzuki, R;Kohno, H;Tanaka, T
通讯作者：
Tanaka, T