Jin Ke, Xiang Yonghua, Tang Jing, Wu Guangchun, Li Junwei, Xiao Huaichun, Li Chunwang, Chen Yuxiang, Zhao Jingfeng
Tumour Biol. 2014 Feb;35(2):1503-10. doi: 10.1007/s13277-013-1207-z.
miR-34a has been identified as a tumor suppressor in several tumors, but its involvement in gallbladder cancer (GBC) has not been reported. In this study, the miR-34a level and telomere length were measured in 77 gallbladder adenocarcinomas and 36 peritumoral tissues by real-time PCR. Forced miR-34a expression was established by an adenovirus carrying a miR-34a expression cassette. The colony-forming ability of isolated CD44+CD133+ GBC tumor stem-like cells was measured by matrigel colony assay. The xenograft tumor models were established by inoculating nude mice with CD44+CD133+cells. Results showed that significantly lower miR-34a expression and longer telomere length were observed in gallbladder adenocarcinoma tissues, which correlated with poor prognosis of GBC patients. Forced overexpression of miR-34a inhibited the colony-forming ability of CD44+CD133+ GBC tumor stem-like cells in vitro and xenograft tumor growth in vivo. Injection of Ad-miR-34a downregulated PNUTS expression and reduced telomere length in xenograft GBC tumor cells. In conclusion, miR-34a is a tumor suppressor in gallbladder cancer. Both low miR-34a expression and long telomere length are markers for poor prognosis of patients with gallbladder adenocarcinoma. Our study also suggests that the miR-34a gene could be a target for targeting therapy of GBC.
miR-34a已被确定为多种肿瘤中的肿瘤抑制因子，但它在胆囊癌（GBC）中的作用尚未见报道。在本研究中，通过实时PCR检测了77例胆囊腺癌组织和36例癌旁组织中的miR-34a水平和端粒长度。通过携带miR-34a表达盒的腺病毒建立miR-34a的强制表达。通过基质胶集落试验检测分离的CD44+CD133+ GBC肿瘤干细胞样细胞的集落形成能力。通过给裸鼠接种CD44+CD133+细胞建立异种移植肿瘤模型。结果显示，在胆囊腺癌组织中观察到miR-34a表达显著降低且端粒长度更长，这与GBC患者的不良预后相关。miR-34a的强制过表达在体外抑制了CD44+CD133+ GBC肿瘤干细胞样细胞的集落形成能力，并在体内抑制了异种移植肿瘤的生长。注射Ad-miR-34a可下调异种移植GBC肿瘤细胞中PNUTS的表达并缩短端粒长度。总之，miR-34a是胆囊癌中的一种肿瘤抑制因子。miR-34a低表达和端粒长度长均是胆囊腺癌患者不良预后的标志物。我们的研究还表明，miR-34a基因可能是GBC靶向治疗的一个靶点。
