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microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer
Lijing Zhang, Yujuan Dong, Nana Zhu
1Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Prince of Wales Hospital, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China. zzr-doctor@163.com.
Background:
miR-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).
Methods:
The 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.
Results:
miR-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).
Conclusions:
miR-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.
Insights
MicroRNA-139-5p (miR-139-5p) is downregulated in colorectal cancer (CRC). Restoring miR-139-5p inhibits tumor growth, promotes apoptosis, and arrests cell cycle by targeting NOTCH1.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MicroRNA-139-5p (miR-139-5p) is significantly downregulated in colon tumor tissues.
- This downregulation suggests a potential role in colorectal cancer (CRC) development.
Purpose of the Study:
- To investigate the biological function and molecular mechanisms of miR-139-5p in colorectal cancer.
- To identify the direct target gene and signaling pathway regulated by miR-139-5p.
Main Methods:
- Cell growth, cell cycle, and apoptosis assays were performed in vitro and in vivo.
- Luciferase activity assays and Western blot analysis were used to identify miR-139-5p targets and pathways.
Main Results:
- miR-139-5p expression was significantly lower in primary tumor tissues.
- Ectopic miR-139-5p expression suppressed colon cancer cell proliferation, induced apoptosis, caused G0/G1 cell cycle arrest, and inhibited migration and invasion.
- NOTCH1 was identified as a direct target of miR-139-5p, with inverse correlation in expression.
Conclusions:
- miR-139-5p acts as a tumor suppressor in colorectal cancer.
- It inhibits proliferation and metastasis while promoting apoptosis and cell cycle arrest.
- Targeting the oncogene NOTCH1 is a key mechanism for miR-139-5p's function in CRC.
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