microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer

Abstract

BackgroundmiR-139-5p was identified to be significantly down-regulated in colon tumor tissues by miRNA array. We aimed to clarify its biological function, molecular mechanisms and direct target gene in colorectal cancer (CRC).MethodsThe biological function of miR-139-5p was examined by cell growth, cell cycle and apoptosis analysis in vitro and in vivo. miR-139-5p target gene and signaling pathway was identified by luciferase activity assay and western blot.ResultsmiR-139-5p was significantly down-regulated in primary tumor tissues (P < 0.0001). Ectopic expression of miR-139-5p in colon cancer cell lines significantly suppressed cell growth as evidenced by cell viability assay (P < 0.001) and colony formation assay (P < 0.01) and in xenograft tumor growth in nude mice (P < 0.01). miR-139-5p induced apoptosis (P < 0.01), concomitantly with up-regulation of key apoptosis genes including cleaved caspase-8, caspase-3, caspase-7 and PARP. miR-139-5p also caused cell cycle arrest in G0/G1 phase (P < 0.01), with upregulation of key G0/G1 phase regulators p21Cip1/Waf1 and p27Kip1. Moreover, miR-139-5p inhibited cellular migration (P < 0.001) and invasiveness (P < 0.001) through the inhibition of matrix metalloproteinases (MMP)7 and MMP9. Oncogene NOTCH1 was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression (r = -0.3862, P = 0.0002).ConclusionsmiR-139-5p plays a pivotal role in colon cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis and cell cycle arrest by targeting oncogenic NOTCH1.

miR-139-5p inhibits epithelial–mesenchymal transition, migration and invasion of hepatocellular carcinoma cells by targeting ZEB1 and ZEB2

“…It has been reported that miR-139-5p is the most down-regulated miRNA in colorectal cancer (CRC) tissue [11], and it is frequently down-regulated in invasive breast carcinoma [8]. Consistent with previous studies, we found that miR-139-5p was under-expressed in all five HCC cell lines and in 89.7% of the HCC tissue samples.…”

miR-141 targets ZEB2 to suppress HCC progression

“…Increasing evidence indicates that miRNAs are significant prognostic factors and also potential therapeutic targets for many malignant tumors, including HCC [12][13][14][15]. Zheng et al reported that miR-452 promoted HCC tumorigenesis by targeting cyclin-dependent kinase inhibitor 1B (CDKN1B) [16].…”

MicroRNA‑139 inhibits the proliferation, migration and invasion of gastric cancer cells by directly targeting ρ‑associated protein kinase 1

“…Additionally, miR-139 suppresses epithelial-mesenchymal transition, migration and invasion in hepatocellular carcinoma, and the incidence and severity of pulmonary metastasis in orthotopic liver tumors in mice is also reduced (20,27). Furthermore, Zhang et al (28) revealed that colorectal cancer cell viability, colony formation, nude mice tumor growth, cell migration and invasion are repressed by miR-139, and Luo et al (29) demonstrated that proliferation, invasion and metastasis of laryngeal squamous carcinoma cells are also reduced. miR-139 functions as a tumor suppressor in esophageal squamous cell carcinoma by cell proliferation, migration and invasion inhibition, apoptosis induction and G0/G1 phase cell cycle arrest (22).…”