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Int J Cancer ; 144(11): 2774-2781, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30478850

RESUMO

Micro RNAs (miR) are master regulators of cellular transcriptome. We aimed to investigate the role of miR regulation on tumor radiosensitivity and development of local tumor recurrence by a novel large-scale in vivo loss of function screen. For stable miR silencing, human A431 tumor cells were transduced with lentiviral constructs against 170 validated human miR (miRzip library). Fractionated radiotherapy (5x6Gy) was applied to A431 miRzip library growing s.c. in NCr nude mice. Enrichment of miRZip and miR expression was assessed using multiplexed qRT-PCR. The modulatory effect of miR on tumor and tumor microenvironment response to ionizing radiation was further evaluated by clonogenic survival, apoptosis (Caspase 3/7), DNA double-strand breaks (DSB, nuclear γH2AX foci), tumor microvessel density (MVD), transcriptome and protein analysis. Fractionated irradiation of the A431 miRzip library led to regression of tumors. However, after a latency period, tumors ultimately progressed and formed local recurrences indicating the survival of a subpopulation of miRzip expressing tumor clones. Among the selected miR for subsequent validation studies, loss of miR-29a, miR-100 and miR-155 was found to enhance clonogenic survival, reduce apoptosis and residual γH2AX foci of irradiated tumor cells. Moreover, knockdown of miR increased tumor angiogenesis correlating with elevated VEGF and TGFα expression levels. This phenomenon was most evident after tumor irradiation in vivo suggesting a critical role for tumor-stroma communication in development of the radioresistant phenotype. Engineering radioresistant tumors in vivo by modulating miR expression may lead to identification of critical targets for conquering local therapy failure.


Assuntos
MicroRNAs/genética , Neoplasias/radioterapia , Tolerância a Radiação/genética , Animais , Antagomirs/metabolismo , Linhagem Celular Tumoral , Reparo do DNA/genética , Fracionamento da Dose de Radiação , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Mutação com Perda de Função , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/isolamento & purificação , MicroRNAs/metabolismo , Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
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