Xiao Junjie, Lv Dongchao, Zhou Jinzhe, Bei Yihua, Chen Ting, Hu Muren, Zhou Qiulian, Fu Siyi, Huang Qi
Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China.
Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
Theranostics. 2017 Apr 10;7(7):1901-1913. doi: 10.7150/thno.19168. eCollection 2017.
Dysregulation of microRNAs (miRNAs, miRs) and their putative target genes have been increasingly reported to contribute to colorectal cancer. However, miRNAs that directly target the mutated in colorectal cancer (MCC) gene, a tumor suppressor which is downregulated or inactivated in colorectal cancer, remain largely unknown. By using an array-based miRNA analysis, we identified a group of miRNAs that were dysregulated in human metastatic non-metastatic colorectal cancer tissues. One of these miRNAs, miR-4260, was predicted to target MCC in the miRDB database. Results using human HCT116 and HT29 colorectal cancer cell lines showed that miR-4260 mimic enhanced cell proliferation and migration and reduced apoptosis induced by the chemotherapeutic agent 5-fluorouracil while miR-4260 inhibitor had inverse effects. Furthermore, miR-4260 negatively regulated MCC as well as SMAD4 by directly binding to the 3'untranslational region (3'UTR). Using siRNAs targeting MCC or SMAD4, we showed that upregulation of MCC and SMAD4 was essential to mediate the functional roles of miR-4260 inhibitor in colorectal cancer cells. Our experiments indicated that inhibition of miR-4260 reduced colorectal tumor growth in nude mice subcutaneously implanted with HCT116 cells. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4, strongly suggesting the clinical relevance of targeting miR-4260 in the treatment of colorectal cancer. In summary, we identified miR-4260 as a novel oncomiR for colorectal cancer that targets MCC and SMAD4. Inhibition of miR-4260 can, therefore, be a potential therapeutic strategy for colorectal cancer.
微小RNA（miRNA，miR）及其假定靶基因的失调越来越多地被报道与结直肠癌有关。然而，直接靶向结直肠癌中突变基因（MCC）的miRNA在很大程度上仍不为人所知，MCC是一种肿瘤抑制因子，在结直肠癌中下调或失活。通过基于阵列的miRNA分析，我们鉴定出一组在人转移性和非转移性结直肠癌组织中失调的miRNA。其中一种miRNA，即miR-4260，在miRDB数据库中被预测靶向MCC。使用人HCT116和HT29结直肠癌细胞系的结果表明，miR-4260模拟物增强了细胞增殖和迁移，并减少了化疗药物5-氟尿嘧啶诱导的细胞凋亡，而miR-4260抑制剂则产生相反的效果。此外，miR-4260通过直接结合3'非翻译区（3'UTR）对MCC以及SMAD4进行负调控。使用靶向MCC或SMAD4的小干扰RNA（siRNA），我们表明上调MCC和SMAD4对于介导miR-4260抑制剂在结直肠癌细胞中的功能作用至关重要。我们的实验表明，抑制miR-4260可减少皮下植入HCT116细胞的裸鼠体内结直肠肿瘤的生长。值得注意的是，在人结直肠癌组织中miR-4260增加，同时MCC和SMAD4下调，这强烈表明靶向miR-4260在结直肠癌治疗中的临床相关性。总之，我们鉴定出miR-4260是一种靶向MCC和SMAD4的新型结直肠癌致癌miR。因此，抑制miR-4260可能是结直肠癌的一种潜在治疗策略。
