Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Mol Cancer Res. 2013 Sep;11(9):1051-60. doi: 10.1158/1541-7786.MCR-13-0061. Epub 2013 May 30.
Dysregulated microRNA (miRNA) expression was profiled through a miRNA array comparison between human colorectal cancer tumors and their adjacent normal tissues. Specifically, using laser capture micro-dissection, miR-133a was shown to be significantly downregulated in primary colorectal cancer specimens compared with matched adjacent normal tissue. Ectopic expression of miR-133a significantly suppressed colorectal cancer cell growth in vitro and in vivo. Cell-cycle analysis revealed that miR-133a induced a G0/G1-phase arrest, concomitant with the upregulation of the key G1-phase regulator p21(Cip1). We further revealed that miR-133a markedly increased p53 protein and induced p21(Cip1) transcription. Studies in silico revealed that the 3'UTR of the ring finger and FYVE-like domain containing E3-ubiquitin protein ligase (RFFL), which regulates p53 protein, contains an evolutionarily conserved miR-133a binding site. miR-133a repressed RFFL-3'UTR reporter activity and reduced RFFL protein levels, indicating that miR-133a directly bound to RFFL mRNA and inhibited RFFL translation. Moreover, miR-133a sensitized colon cancer cells to doxorubicin and oxaliplatin by enhancing apoptosis and inhibiting cell proliferation. These data add weight to the significance of miR-133a in the development of CRC.
miR-133a serves as a potential tumor suppressor upstream of p53 in colorectal cancer and may sensitize cells to therapeutics.
通过人结直肠癌肿瘤与其相邻正常组织之间的 miRNA 阵列比较来分析失调的 microRNA (miRNA) 表达。具体来说，使用激光捕获微切割，miR-133a 显示在原发性结直肠癌标本中与匹配的相邻正常组织相比显著下调。miR-133a 的异位表达显着抑制结直肠癌细胞在体外和体内的生长。细胞周期分析显示，miR-133a 诱导 G0/G1 期停滞，同时上调关键的 G1 期调节剂 p21(Cip1)。我们进一步揭示，miR-133a 显著增加了 p53 蛋白并诱导了 p21(Cip1)转录。计算机研究表明，含有调节 p53 蛋白的环指和 FYVE 样结构域的 E3 泛素蛋白连接酶 (RFFL) 的 3'UTR 包含一个进化上保守的 miR-133a 结合位点。miR-133a 抑制 RFFL-3'UTR 报告基因活性并降低 RFFL 蛋白水平，表明 miR-133a 直接与 RFFL mRNA 结合并抑制 RFFL 翻译。此外，miR-133a 通过增强细胞凋亡和抑制细胞增殖使结肠癌对阿霉素和奥沙利铂敏感。这些数据增加了 miR-133a 在 CRC 发展中的重要性。
miR-133a 作为结直肠癌中 p53 的上游潜在肿瘤抑制因子，可能使细胞对治疗敏感。
