RESUMO
As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-ß signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-ß activates miR-1269 via Sox4, while miR-1269a enhances TGF-ß signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.
Assuntos
Neoplasias Colorretais/genética , Retroalimentação Fisiológica , MicroRNAs/genética , Recidiva Local de Neoplasia/genética , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Imunoprecipitação da Cromatina , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Imunofluorescência , Células HCT116 , Células HT29 , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Transplante de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição SOXC/metabolismo , Proteína Smad7/metabolismo , Fatores de Transcrição/metabolismo , Adulto JovemRESUMO
Lateral Inhibition (LI) is a widely conserved patterning mechanism in biological systems across species. Distinct from better-known Turing patterns, LI depend on cell-cell contact rather than diffusion. We built an in silico genetic circuit model to analyze the dynamic properties of LI. The model revealed that LI amplifies differences between neighboring cells to push them into opposite states, hence forming stable 2-D patterns. Inspired by this insight, we designed and implemented an electronic circuit that recapitulates LI patterning dynamics. This biomimetic system serve as a physical model to elucidate the design principle of generating robust patterning through spatial feedback, regardless of the underlying devices being biological or electrical.