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Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

Hu, Qingsong; Ye, Youqiong; Chan, Li-Chuan; Li, Yajuan; Liang, Ke; Lin, Aifu; Egranov, Sergey D; Zhang, Yaohua; Xia, Weiya; Gong, Jing; Pan, Yinghong; Chatterjee, Sujash S; Yao, Jun; Evans, Kurt W; Nguyen, Tina K; Park, Peter K; Liu, Jiewei; Coarfa, Cristian; Donepudi, Sri Ramya; Putluri, Vasanta; Putluri, Nagireddy; Sreekumar, Arun; Ambati, Chandrashekar R; Hawke, David H; Marks, Jeffrey R; Gunaratne, Preethi H; Caudle, Abigail S; Sahin, Aysegul A; Hortobagyi, Gabriel N; Meric-Bernstam, Funda; Chen, Lieping; Yu, Dihua; Hung, Mien-Chie; Curran, Michael A; Han, Leng; Lin, Chunru; Yang, Liuqing.
Nat Immunol; 20(7): 835-851, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31160797
How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.
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