Zhang Lijing, Dong Yujuan, Zhu Nana, Tsoi Ho, Zhao Zengren, Wu Chung Wah, Wang Kunning, Zheng Shu, Ng Simon Sm, Chan Francis Kl, Sung Joseph Jy, Yu Jun
Institute 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.
Mol Cancer. 2014 May 26;13:124. doi: 10.1186/1476-4598-13-124.
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).
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.
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).
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.
通过miRNA芯片鉴定发现，miR-139-5p在结肠肿瘤组织中显著下调。我们旨在阐明其在结直肠癌（CRC）中的生物学功能、分子机制及直接靶基因。
通过体外和体内的细胞生长、细胞周期及凋亡分析来检测miR-139-5p的生物学功能。通过荧光素酶活性测定和蛋白质印迹法鉴定miR-139-5p的靶基因和信号通路。
miR-139-5p在原发性肿瘤组织中显著下调（P < 0.0001）。结肠癌细胞系中miR-139-5p的异位表达显著抑制细胞生长，细胞活力测定（P < 0.001）、集落形成测定（P < 0.01）及裸鼠异种移植瘤生长实验（P < 0.01）均证明了这一点。miR-139-5p诱导细胞凋亡（P < 0.01），同时关键凋亡基因包括裂解的半胱天冬酶-8、半胱天冬酶-3、半胱天冬酶-7和聚（ADP-核糖）聚合酶（PARP）上调。miR-139-5p还导致细胞周期停滞在G0/G1期（P < 0.01），关键的G0/G1期调节因子p21Cip1/Waf1和p27Kip1上调。此外，miR-139-5p通过抑制基质金属蛋白酶（MMP）7和MMP9来抑制细胞迁移（P < 0.001）和侵袭（P < 0.001）。致癌基因NOTCH1被发现是miR-139-5p的一个假定靶标，其与miR-139-5p表达呈负相关（r = -0.3862，P = 0.0002）。
miR-139-5p通过靶向致癌基因NOTCH1抑制细胞增殖、转移，促进凋亡和细胞周期停滞，在结肠癌中起关键作用。
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