Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation.
Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation.
复制标题
泛癌症分析揭示了TAp63调节的致癌lncRNA，通过AKT激活促进癌症进展。
DOI：
10.1038/s41467-020-18973-w
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发表时间：
2020-10-14
影响因子：
16.6
通讯作者：
Flores ER
中科院分区：
文献类型：
--
作者：
Napoli M;Li X;Ackerman HD;Deshpande AA;Barannikov I;Pisegna MA;Bedrosian I;Mitsch J;Quinlan P;Thompson A;Rajapakshe K;Coarfa C;Gunaratne PH;Marchion DC;Magliocco AM;Tsai KY;Flores ER
在多种人类癌症中最常见的遗传改变是TP 53突变和PI 3 K/AKT通路的激活，这两个事件对癌症进展至关重要。TP 53中的突变导致肿瘤和转移抑制因子TAp 63（p53家族成员）的抑制。通过在TAp 63转移性乳腺癌小鼠模型和人乳腺癌进展模型之间进行小鼠-人跨物种分析，我们鉴定了两种TAp 63调节的致癌lncRNA，TROLL-2和TROLL-3。此外，使用人类癌症和多种肿瘤进展小鼠模型的泛癌症分析，我们揭示了这两种lncRNA通过调节其效应子WDR 26经由穿梭蛋白NOLC 1的细胞核至细胞质易位来诱导AKT的活化以促进癌症进展。我们的数据为实施这些lncRNA和WDR 26作为治疗靶点用于治疗依赖于突变型TP 53和/或PI 3 K/AKT通路的人肿瘤提供了临床前基本原理。TP 53的突变和PI 3 K/AKT通路的过度活化是多种人类肿瘤类型中癌症进展的两个最常见的驱动因素。在这里，作者确定了两个TAp 63调节的长非编码RNA，TROLL-2和TROLL-3，它们连接这些致癌途径，从而促进各种癌症类型中的肿瘤和转移形成。
The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway. Mutations in TP53 and hyperactivation of the PI3K/AKT pathway are the two most frequent drivers of cancer progression across multiple human tumour types. Here, the authors identify two TAp63 regulated long non-coding RNAs, TROLL-2 and TROLL-3, that connect these oncogenic pathways, thus promoting tumour and metastasis formation in a wide variety of cancer types.
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影响因子：
--
作者：
Bhardwaj A;Singh H;Rajapakshe K;Tachibana K;Ganesan N;Pan Y;Gunaratne PH;Coarfa C;Bedrosian I
通讯作者：
Bedrosian I
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
10.5
作者：
Cabili, Moran N.;Trapnell, Cole;Rinn, John L.
通讯作者：
Rinn, John L.
影响因子：
--
作者：
Alt EU;Barabadi Z;Pfnür A;Ochoa JE;Daneshimehr F;Lang LM;Lin D;Braun SE;Chandrasekar B;Izadpanah R
通讯作者：
Izadpanah R
影响因子：
50.3
作者：
Girardini, Javier E.;Napoli, Marco;Del Sal, Giannino
通讯作者：
Del Sal, Giannino