Zhu Zheng, Gao Wentao, Qian Zhuyin, Miao Yi
Department of General Surgery, The First Clinic Medical College of Nanjing Medical University, Nanjing, China.
Acta Biochim Biophys Sin (Shanghai). 2009 May;41(5):407-13. doi: 10.1093/abbs/gmp023.
MicroRNAs (miRNAs) are small non-coding RNAs of 20-22 nucleotides (nts) and constitute a novel class of gene regulators that negatively regulate gene expression at the post-transcriptional level. The expression of miRNA is deregulated in many types of cancers. Alterations in miRNA expression may be an important contributor to the development of pancreatic carcinoma. We hypothesized that genetic variations in miRNA genes were associated with pancreatic carcinoma and analyzed genomic sequences coding for the precursors of eight miRNA genes in both pancreatic carcinoma tissues and cancer cell lines. Four novel mutations in primary miRNA transcripts were identified. TaqMan miRNA assays showed that miR-21 was significantly overexpressed in 20 pancreatic carcinomas and 6 cancer cell lines compared with paired benign tissues and normal pancreas. Two mutations of miR-21 did not notably alter the activity of the promoter of the miRNA gene. Although most of these mutations seem to have no effect on miRNA processing, an A-G mutation at 29-nt downstream of pre-miR-21 led to a conformational change of the secondary structure close to the stem reaching into the pre-miR-21 and a relative reduction of the mature miR-21 expression in vivo. These results suggested that miRNA might play an important role in pancreatic tumorigenesis, but the molecular mechanism underlying the particular sequence variations in miRNA that can cause aberrant expression remains to be determined.
微小RNA（miRNA）是一类长度为20 - 22个核苷酸的小型非编码RNA，构成了一类新型的基因调控因子，可在转录后水平负向调控基因表达。miRNA的表达在多种癌症类型中失调。miRNA表达的改变可能是胰腺癌发生发展的一个重要因素。我们推测miRNA基因的遗传变异与胰腺癌相关，并分析了胰腺癌组织和癌细胞系中8个miRNA基因前体的编码基因组序列。在初级miRNA转录本中鉴定出4个新的突变。TaqMan miRNA分析显示，与配对的良性组织和正常胰腺相比，miR - 21在20例胰腺癌和6个癌细胞系中显著过表达。miR - 21的两个突变并未显著改变miRNA基因启动子的活性。尽管这些突变大多似乎对miRNA加工没有影响，但pre - miR - 21下游29个核苷酸处的A - G突变导致靠近茎部进入pre - miR - 21的二级结构发生构象变化，并使体内成熟miR - 21的表达相对降低。这些结果表明，miRNA可能在胰腺癌发生中起重要作用，但导致异常表达的miRNA特定序列变异的分子机制仍有待确定。
