Creas and immortalized by expression of the catalytic subunit of telomerase (hTERT) [15]. hTERT can immortalize primary human cells without changing their phenotypic properties or causing cancer-associated changes [16?9]. Mounting evidence now suggests that acinar-to-ductal metaplasia plays a vital role in the initiation of pancreatic cancer development [20?3]. hTERT-HPNE cells have properties similar to that of the intermediary cells produced during acinar-to-ductal metaplasia. The properties shared by hTERT-HPNE and these intermediary cells included their undifferentiated phenotype and the ability to differentiate into pancreatic ductal cells [24]. It seems that PANC-1 and hTERT-HPNE both possess the characteristic of being intermediary or undifferentiated cells. Thus, some target genes up-regulated by miRNA in the two cell lines may participate in tumorigenesis. It is often reported that miRNAs negatively regulate posttranscriptional gene expression by inhibiting translation and causing degradation of the target mRNA [13], primarily through base-pairing interactions, which leads to either mRNA degradation or translational inhibition, depending upon the degree of match between the “seed sequence” (positions 2? at the 59 side) of the miRNA and 39-UTR of the mRNA. When the seed sequence perfectly or partially matches with target 39-UTR of the mRNA, then it may lead to degradation of the mRNA or inhibit translation [25?8]. The expression profiles of miRNAs are frequently altered in tumors, and in some cases, a reduction in the expression of miRNA may cause increased expression of the oncogenic target genes [29]. The biological functions of miRNAs are highly dependent on cellular context, which may be due to the differential expression of their target mRNAs. It has also beendemonstrated that cellular proteins can also regulate RNAi. Therefore, according to the results of our experiments using dynamic monitoring of miRNA function, the classic theory that miRNAs negatively regulate gene expression by inhibiting translation and causing degradation of the target mRNA is not completely correct. The characteristic of high heterogeneity demonstrates that the abundance of miRNA is influenced by various factors such as different cell origins, cellular metabolism, antigen expression, cellular productions, and so on. When miRNA abundance is relatively low, it may activate other signal transduction pathways or induce some factors promoting target gene upregulation, eventually leading to the overexpression of target genes. On the other hand, AU-rich elements (AREs) and miRNA target sites are conserved sequences in mRNA 39UTRs that control gene expression posttranscriptionally. In 2007, Vasudevan et al found that the TNFa ARE recruits miR369-3 to mediate translation up-regulation in serum-starved conditions and to cause repression in synchronized proliferating cells [30]. miRNAs oscillate between repression and activation in coordination with the cell cycle: In proliferating cells they repress translation, whereas in G1/G0 arrest (which often precedes differentiation), they mediate activation. This regulation occurs on at least two levels. First, recruitment of the microRNP reflects both its expression level and its ability to productively Pleuromutilin interact with mRNA target sites. Second, the AGO2 complex must be subject to modification because tethered AGO2 differentially regulates translation according to cell 301353-96-8 growth conditions. Thus, based on our findings,.Creas and immortalized by expression of the catalytic subunit of telomerase (hTERT) [15]. hTERT can immortalize primary human cells without changing their phenotypic properties or causing cancer-associated changes [16?9]. Mounting evidence now suggests that acinar-to-ductal metaplasia plays a vital role in the initiation of pancreatic cancer development [20?3]. hTERT-HPNE cells have properties similar to that of the intermediary cells produced during acinar-to-ductal metaplasia. The properties shared by hTERT-HPNE and these intermediary cells included their undifferentiated phenotype and the ability to differentiate into pancreatic ductal cells [24]. It seems that PANC-1 and hTERT-HPNE both possess the characteristic of being intermediary or undifferentiated cells. Thus, some target genes up-regulated by miRNA in the two cell lines may participate in tumorigenesis. It is often reported that miRNAs negatively regulate posttranscriptional gene expression by inhibiting translation and causing degradation of the target mRNA [13], primarily through base-pairing interactions, which leads to either mRNA degradation or translational inhibition, depending upon the degree of match between the “seed sequence” (positions 2? at the 59 side) of the miRNA and 39-UTR of the mRNA. When the seed sequence perfectly or partially matches with target 39-UTR of the mRNA, then it may lead to degradation of the mRNA or inhibit translation [25?8]. The expression profiles of miRNAs are frequently altered in tumors, and in some cases, a reduction in the expression of miRNA may cause increased expression of the oncogenic target genes [29]. The biological functions of miRNAs are highly dependent on cellular context, which may be due to the differential expression of their target mRNAs. It has also beendemonstrated that cellular proteins can also regulate RNAi. Therefore, according to the results of our experiments using dynamic monitoring of miRNA function, the classic theory that miRNAs negatively regulate gene expression by inhibiting translation and causing degradation of the target mRNA is not completely correct. The characteristic of high heterogeneity demonstrates that the abundance of miRNA is influenced by various factors such as different cell origins, cellular metabolism, antigen expression, cellular productions, and so on. When miRNA abundance is relatively low, it may activate other signal transduction pathways or induce some factors promoting target gene upregulation, eventually leading to the overexpression of target genes. On the other hand, AU-rich elements (AREs) and miRNA target sites are conserved sequences in mRNA 39UTRs that control gene expression posttranscriptionally. In 2007, Vasudevan et al found that the TNFa ARE recruits miR369-3 to mediate translation up-regulation in serum-starved conditions and to cause repression in synchronized proliferating cells [30]. miRNAs oscillate between repression and activation in coordination with the cell cycle: In proliferating cells they repress translation, whereas in G1/G0 arrest (which often precedes differentiation), they mediate activation. This regulation occurs on at least two levels. First, recruitment of the microRNP reflects both its expression level and its ability to productively interact with mRNA target sites. Second, the AGO2 complex must be subject to modification because tethered AGO2 differentially regulates translation according to cell growth conditions. Thus, based on our findings,.
