Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth.
Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth.
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DOI：
10.26508/lsa.201800190
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发表时间：
2018-10
影响因子：
4.4
通讯作者：
Ostrowski MC
中科院分区：
文献类型：
--
作者：
Pitarresi JR;Liu X;Avendano A;Thies KA;Sizemore GM;Hammer AM;Hildreth BE 3rd;Wang DJ;Steck SA;Donohue S;Cuitiño MC;Kladney RD;Mace TA;Chang JJ;Ennis CS;Li H;Reeves RH;Blackshaw S;Zhang J;Yu L;Fernandez SA;Frankel WL;Bloomston M;Rosol TJ;Lesinski GB;Konieczny SF;Guttridge DC;Rustgi AK;Leone G;Song JW;Wu J;Ostrowski MC
Disrupting paracrine Hedgehog signaling in pancreatic cancer stroma through genetic deletion of fibroblast Smoothened leads to proteasomal degradation of fibroblast PTEN and accelerates tumor growth. The contribution of the tumor microenvironment to pancreatic ductal adenocarcinoma (PDAC) development is currently unclear. We therefore examined the consequences of disrupting paracrine Hedgehog (HH) signaling in PDAC stroma. Herein, we show that ablation of the key HH signaling gene Smoothened (Smo) in stromal fibroblasts led to increased proliferation of pancreatic tumor cells. Furthermore, Smo deletion resulted in proteasomal degradation of the tumor suppressor PTEN and activation of oncogenic protein kinase B (AKT) in fibroblasts. An unbiased proteomic screen identified RNF5 as a novel E3 ubiquitin ligase responsible for degradation of phosphatase and tensin homolog (PTEN) in Smo-null fibroblasts. Ring Finger Protein 5 (Rnf5) knockdown or pharmacological inhibition of glycogen synthase kinase 3β (GSKβ), the kinase that marks PTEN for ubiquitination, rescued PTEN levels and reversed the oncogenic phenotype, identifying a new node of PTEN regulation. In PDAC patients, low stromal PTEN correlated with reduced overall survival. Mechanistically, PTEN loss decreased hydraulic permeability of the extracellular matrix, which was reversed by hyaluronidase treatment. These results define non-cell autonomous tumor-promoting mechanisms activated by disruption of the HH/PTEN axis and identifies new targets for restoring stromal tumor-suppressive functions.
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影响因子：
50.3
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
通讯作者：
Kalluri R
影响因子：
50.3
作者：
Chen M;Pratt CP;Zeeman ME;Schultz N;Taylor BS;O'Neill A;Castillo-Martin M;Nowak DG;Naguib A;Grace DM;Murn J;Navin N;Atwal GS;Sander C;Gerald WL;Cordon-Cardo C;Newton AC;Carver BS;Trotman LC
通讯作者：
Trotman LC
影响因子：
11.5
作者：
Ruch, Joshua M.;Kim, Edward J.
通讯作者：
Kim, Edward J.
影响因子：
64.8
作者：
Jia, JH;Amanal, K;Jiang, J
通讯作者：
Jiang, J
影响因子：
11.2
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.