Let-7a suppresses glioma cell proliferation and invasion through TGF-beta/Smad3 signaling pathway by targeting HMGA2

摘要

It has been shown that let-7a was associated with the tumorigenesis of glioma. Our study was designed to infer how let-7a targets high-mobility AT-hook 2 (HMGA2) and suppresses glioma cell proliferation, invasion, and migration. Glioma tissues from 60 glioma patients and 10 normal brain tissues were collected in this study. Real-time quantitative reverse transcription-PCR (qRT-PCR) and in situ hybridization were used to detect the expression levels of let-7a in tissues and cells. The HMGA2 and the proteins related to transforming growth factor-beta (TGF-beta)/Smad3 signaling pathway were measured by immunohistochemistry and western blot. Glioma U87 cells were transfected with either let-7a mimics, HMGA2 small interfering RNA (siRNA), let-7a mimics + HMGA2, HMGA2, or scramble. A cell counting kit-8 (CCK-8) assay was used to detect and compare the difference among various transfection groups. Glioma tumor xenograft models on mice were built to evaluate the effects of let-7a and HMGA2 siRNA on glioma tumors in vivo. The expression level of let-7a significantly downregulated in glioma tissues, while the HMGA2 positive expression rate notably increased compared with those in normal brain tissues (all P < 0.05). Moreover, the expression levels of let-7a and HMGA2 were correlated with glioma grades (all P < 0.05). The proliferation of U87 cells transfected with let-7a mimics or HMGA2 siRNA was significantly inhibited in comparison to the blank control group and the apoptosis rates of U87 cells transfected with let-7a mimics or HMGA2 siRNA were significantly higher than those in the blank control group (all P < 0.05). Let-7a or HMGA2 siRNA could remarkably attenuate the invasion and migration ability of glioma cells (all P < 0.05). Apart from that, over-expressed exogenous HMGA2 could reverse the inhibition of glioma cell metastasis and proliferation induced by let-7a. As suggested by immunohistochemistry and western blot, the expression levels of TGF-beta 1 and p-Smad3 significantly decreased compared with the blank or scramble group (all P < 0.05). Thus, let-7a and HMGA2 siRNA could effectively suppress the growth of tumors in glioma xenograft models. Let-7a may suppress the proliferation and invasion of glioma cells through mediating TGF-beta/Smad3 signaling pathway by targeting HMGA2.