Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

MicroRNA-137, a HMGA1 target, suppresses cell invasion and metastasis of colorectal carcinoma by directly targeting FMNL2 (#139)

Li Liang 1 , Xianzheng Li 1 , Xiaojing Zhang 1 , Zhenbing Lv 1 , Yanqing Ding 1
  1. Southern Medical University, Guangzhou city, guang, China

Background & Aims: FMNL2, a member of diaphanous-related formins, has been strongly associated with tumor progression but the post-transcriptional regulatory mechanism of FMNL2 remains unknown. Our study aimed to investigate whether increased FMNL2 expression was mediated by microRNAs in colorectal carcinoma (CRC). Methods: Real-time PCR or Western blot was used to detect expression levels of miR-137, HMGA1 and FMNL2 in CRC cells and tissues. The in vitro and in vivo functional effect of miR-137 was examined further. Luciferase reporter assay was conducted to confirm the associations between miR-137 and FMNL2 3’UTR, HMGA1 and miR-137 promoter. ChIP was used to assess direct binding of HMGA1 to miR-137 promoter. Results: miR-137 and miR-142-3p were initially selected as potential miRNAs targeting FMNL2 based on bioinformatic predictions. But only miR-137 demonstrated significant inverse correlation with FMNL2 protein level in CRC cell lines and tissues. FMNL2 was a target gene of miR-137, and miR-137 could inhibit cell proliferation, invasion in vitro, hepatic and intestinal metastases in vivo by targeting FMNL2. The study further proved that HMGA1 enhanced miR-137 transcription by binding its promoter, subsequently down-regulating FMNL2 expression. miR-137 also inhibited the activation of p-MAPK and p-Akt, followed by the suppression of MMP2, MMP9 and VEGF. MiR-137 decreased cell invasiveness by inhibiting PI3K/Akt and MAPK/ERK pathways. Conclusions: Our findings reveal a novel mechanism of post-transcriptional regulation of FMNL2 expression. miR-137, induced by its upstream transcription factor HMGA1, can suppress invasion and metastasis of CRC by regulating its direct target FMNL2, at least in part through inhibiting PI3K/Akt and MAPK/ERK pathways.