miR-9 targets CXCR4 and functions as a potential tumor suppressor in nasopharyngeal carcinoma
Menée sur des échantillons tumoraux prélevés sur des patients chinois atteints d'un carcinome du rhino-pharynx, puis in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en réprimant l'expression du gène CXCR4, le micro-ARN miR-9 joue un rôle de suppresseur de tumeurs
MicroRNA (miRNA) deregulation and pathway alterations have been implicated in nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer widely prevalent in southern China. In this study, we report that miR-9 is commonly downregulated in NPC specimens and NPC cell lines with important functional consequences. The reduced expression of miR-9 was inversely correlated with clinical stages and marked the progression from locoregional to metastatic tumors. The CpG island hypermethylation contributed to miR-9 silencing in NPC cell lines and tissues. Ectopic expression of miR-9 dramatically inhibited the proliferative, migratory and invasive capacities of NPC cells in vitro and in vivo. We found that miR-9 strongly reduced the expression of CXCR4 in NPC cells. Luciferase assay demonstrated that miR-9 could directly bind to the 3’-untranslated region of CXCR4. Similar to the restoring miR-9 expression, CXCR4 downregulation inhibited cell growth, migration and invasion, whereas CXCR4 overexpression rescued the suppressive effect of miR-9. Mechanistic investigations revealed that CXCR4 functionally mediated the SDF-1-stimulated activation of p38 MAPK pathway in NPC cells with miR-9 downregulation or CXCR4 overexpression. In clinical specimens, CXCR4 and phospho-p38 were widely overexpressed, and the levels increased with the progression from locoregional to metastatic tumors in NPC tissues. The levels of CXCR4 were inversely correlated with miR-9 or phospho-p38 expression. Taken together, our results indicate that miR-9 functions as a tumor suppressive miRNA in NPC, and that its suppressive effects are mediated chiefly by repressing CXCR4 expression.
http://carcin.oxfordjournals.org/content/early/2013/10/28/carcin.bgt354.abstract 2013