MicroRNA-34a targets FMNL2 and E2F5 and suppresses the progression of colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies. Increasing evidences indicate that dysregulation of miRNAs is a frequent event in CRC and contributes to the pathogenesis of CRC. In this study, we found that over-expression of miR-34a inhibited cell proliferation and invasion, induced a cell cycle arrest and triggered apoptosis, while knockdown of miR-34a showed the opposite effects. Moreover, ectopic miR-34a suppressed tumor growth and metastasis of CRC cells in vivo. FMNL2 and E2F5 were identified as direct targets of miR-34a. Reintroduction of FMNL2 or E2F5 without 3'UTR region reversed the inhibitory effects of miR-34a on cell proliferation and invasion. MiR-34a was down-regulated in CRC cells and inversely correlated with FMNL2 and E2F5 expressions. Our study suggests that miR-34a is an important tumor suppressor of CRC progression by targeting FMNL2 and E2F5, thus providing new insight into the molecular mechanisms underlying CRC progression and establishing a strong potential for the application of miR-34a as a novel therapeutic marker against CRC.

Lu G ，Sun Y ，An S ，Xin S ，Ren X ，Zhang D ，Wu P ，Liao W ，Ding Y ，Liang L ... -  《-》

MicroRNA-137, an HMGA1 target, suppresses colorectal cancer cell invasion and metastasis in mice by directly targeting FMNL2.

Formin-like (FMNL)2 is up-regulated in colorectal tumors and has been associated with tumor progression, but little is known about regulatory mechanisms. We investigated whether microRNAs regulate levels of FMNL2 in colorectal cancer (CRC) cells. We used real-time polymerase chain reaction and immunoblot analyses to measure levels of miR-137, high-mobility group AT-hook (HMGA)1, and FMNL2 in CRC cells and tissue samples from patients (n = 50). We used luciferase reporter assays to determine the association between miR-137 and the FMNL2 3' untranslated region, and HMGA1 and the miR-137 promoter. Chromatin immunoprecipitation assays were used to assess direct binding of HMGA1 to the miR-137 promoter. miR-137 and miR-142-3p were predicted to bind FMNL2 based on bioinformatic data. Only the level of miR-137 had a significant inverse correlation with the level of FMNL2 protein in CRC cell lines and tissues. FMNL2 messenger RNA was targeted by miR-137; expression of miR-137 inhibited proliferation and invasion by CRC cells in vitro, and metastasis to liver and intestine by CRC xenografts in nude mice. HMGA1 bound to the promoter of miR-137 and activated its transcription, which reduced levels of FMNL2 in CRC cells. Ectopic expression of miR-137 in CRC cells inhibited phosphorylation of mitogen-activated protein kinase (MAPK) and Akt, which reduced levels of matrix metalloproteinase 2, matrix metalloproteinase 9, and vascular endothelial growth factor; it also reduced invasiveness of CRC cells, inhibiting signaling via phosphatidylinositol-4,5-bisphosphate 3-kinase, Akt, and MAPK. Levels of miR-137 and HMGA1 are reduced, and levels of FMNL2 are increased, in CRC samples compared with adjacent normal mucosa. In CRC cells, miR-137 targets FMNL2 messenger RNA and is regulated by the transcription factor HMGA1. Expression of miR-137 reduces CRC cell invasion in vitro and metastasis of tumor xenografts in mice. FMNL2 appears to activate phosphatidylinositol-4,5-bisphosphate 3-kinase, protein kinase B (Akt), and MAPK signaling pathways.

Liang L ，Li X ，Zhang X ，Lv Z ，He G ，Zhao W ，Ren X ，Li Y ，Bian X ，Liao W ，Liu W ，Yang G ，Ding Y ... -  《-》

MicroRNA-206 functions as a tumor suppressor in colorectal cancer by targeting FMNL2.

Ren XL ，He GY ，Li XM ，Men H ，Yi LZ ，Lu GF ，Xin SN ，Wu PX ，Li YL ，Liao WT ，Ding YQ ，Liang L ... -  《-》

MiR-613 suppresses retinoblastoma cell proliferation, invasion, and tumor formation by targeting E2F5.

Zhang Y ，Zhu X ，Zhu X ，Wu Y ，Liu Y ，Yao B ，Huang Z ... -  《-》

microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis.

Zhang N ，Li X ，Wu CW ，Dong Y ，Cai M ，Mok MT ，Wang H ，Chen J ，Ng SS ，Chen M ，Sung JJ ，Yu J ... -  《-》