Regulation of colorectal carcinoma stemness, growth and metastasis by a miR-200c-Sox2 negative feedback loop mechanism
Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, puis sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du gène Sox2, le micro-ARN miR-200c favorise le processus métastatique
Purpose:To elucidate a novel mechanism of miR-200c in the regulation of stemness, growth and metastasis in colorectal carcinoma (CRC). Experimental Design:Quantitative reverse transcription-PCR was used to quantify miR-200c expression in CRC cell lines and tissues. A luciferase assay was adopted for the target evaluation. The functional effects of miR-200c in CRC cells were assessed either by its forced or inhibited expression using lentiviruses. Results:MiR-200c was statistically lower in CRC clinical specimens and highly metastatic CRC cell lines compared to their counterparts. Sox2 was validated as a target for miR-200c. The knock-down of miR-200c significantly enhanced proliferation, migration and invasion in CRC cell lines, while the up-regulation of miR-200c exhibited an inverse effect. Moreover, rescue of Sox2 expression could abolish the effect of the up-regulation of miR-200c. In addition, the reduction of miR-200c increased the expression of CRC stem cell markers and the sphere-forming capacity of CRC cell lines. Further study has shown that miR-200c and Sox2 reciprocally control their expression through a feedback loop. MiR-200c suppresses the expression of Sox2 to block the activity of the PI3K-AKT pathway. Conclusions:Our findings indicate that miR-200c regulates Sox2 expression through a feedback loop and is associated with CRC stemness, growth and metastasis.