Su Hang, Yang Jian-Rong, Xu Teng, Huang Jun, Xu Li, Yuan Yunfei, Zhuang Shi-Mei
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
Cancer Res. 2009 Feb 1;69(3):1135-42. doi: 10.1158/0008-5472.CAN-08-2886. Epub 2009 Jan 20.
Although aberrant microRNA (miRNA) expressions have been observed in different types of cancer, their pathophysiologic role and their relevance to tumorigenesis are still largely unknown. In this study, we first evaluated the expression of 308 miRNAs in human hepatocellular carcinoma (HCC) and normal hepatic tissues and identified 29 differentially expressed miRNAs in HCC tissues. miR-101, a significantly down-regulated miRNA, was further studied in greater detail because the signal pathway(s) regulated by miR-101 and the role of miR-101 in tumorigenesis have not yet been elucidated. Interestingly, decreased expression of miR-101 was found in all six hepatoma cell lines examined and in as high as 94.1% of HCC tissues, compared with their nontumor counterparts. Furthermore, ectopic expression of miR-101 dramatically suppressed the ability of hepatoma cells to form colonies in vitro and to develop tumors in nude mice. We also found that miR-101 could sensitize hepatoma cell lines to both serum starvation- and chemotherapeutic drug-induced apoptosis. Further investigation revealed that miR-101 significantly repressed the expression of luciferase carrying the 3'-untranslated region of Mcl-1 and reduced the endogenous protein level of Mcl-1, whereas the miR-101 inhibitor obviously up-regulated Mcl-1 expression and inhibited cell apoptosis. Moreover, silencing of Mcl-1 phenocopied the effect of miR-101 and forced expression of Mcl-1 could reverse the proapoptotic effect of miR-101. These results indicate that miR-101 may exert its proapoptotic function via targeting Mcl-1. Taken together, our data suggest an important role of miR-101 in the molecular etiology of cancer and implicate the potential application of miR-101 in cancer therapy.
尽管在不同类型的癌症中已观察到异常的微小RNA（miRNA）表达，但其病理生理作用及其与肿瘤发生的相关性仍大多未知。在本研究中，我们首先评估了308种miRNA在人类肝细胞癌（HCC）和正常肝组织中的表达，并在HCC组织中鉴定出29种差异表达的miRNA。miR-101是一种显著下调的miRNA，由于其调控的信号通路以及在肿瘤发生中的作用尚未阐明，因此对其进行了更深入的研究。有趣的是，在所检测的所有六种肝癌细胞系以及高达94.1%的HCC组织中，均发现miR-101表达降低，与其非肿瘤对应组织相比。此外，miR-101的异位表达显著抑制了肝癌细胞在体外形成集落以及在裸鼠体内形成肿瘤的能力。我们还发现miR-101可使肝癌细胞系对血清饥饿和化疗药物诱导的凋亡敏感。进一步研究表明，miR-101显著抑制携带Mcl-1 3'-非翻译区的荧光素酶的表达，并降低Mcl-1的内源性蛋白水平，而miR-101抑制剂则明显上调Mcl-1表达并抑制细胞凋亡。此外，Mcl-1的沉默模拟了miR-101的作用，而Mcl-1的强制表达可逆转miR-101的促凋亡作用。这些结果表明，miR-101可能通过靶向Mcl-1发挥其促凋亡功能。综上所述，我们的数据表明miR-101在癌症分子病因学中具有重要作用，并暗示了miR-101在癌症治疗中的潜在应用。
