Abstract
microRNAs (miRs) modulate the expression levels of mRNAs and proteins and can thus contribute to cancer initiation and progression. In addition to their intracelluar function, miRs are released from cells and shed into the circulation. We postulated that circulating miRs could provide insight into pathways altered during cancer progression and may indicate responses to treatment. Here we focus on pancreatic cancer malignant progression. We report that changes in miR expression patterns during progression of normal tissues to invasive pancreatic adenocarcinoma in the p48-Cre/LSL-KrasG12D mouse model mirrors the miR changes observed in human pancreatic cancer tissues. miR-148a/b and miR-375 expression were found decreased whereas miR-10, miR-21, miR-100 and miR-155 were increased when comparing normal tissues, premalignant lesions and invasive carcinoma in the mouse model. Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated. Quantitation of nine microRNAs in plasma samples from patients distinguished pancreatic cancers from other cancers as well as non-cancerous pancreatic disease. Finally, gemcitabine treatment of control animals and p48-Cre/LSL-KrasG12D animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues. These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.
Highlights
MicroRNAs are small, non-coding RNAs that play a significant role in controlling the activities of cellular pathways both in physiology and pathology
The distinct function of miRs in different cancers has become more obvious over the past years [2,3], and many studies show that miR signatures can be used to distinguish different cancers [4,5,6,7] prognoses [8,9,10,11,12,13] or reveal potential targets [14] as well as altered signaling pathways [15]
A panel of miRs consistently up- or down-regulated across different studies in human pancreatic cancer tissues relative to normal pancreatic tissues was selected from literature and data base searches
Summary
MicroRNAs (miRNAs or miRs) are small, non-coding RNAs that play a significant role in controlling the activities of cellular pathways both in physiology and pathology (see e.g. [1]). A comparison of miR and mRNA profiles of primary and metastatic cancer lesions showed that miRs provided a more reliable and distinctive signature than mRNAs and found that miR signatures were superior to mRNAs in identifying the organ source of metastases of unknown origin [16,17] Beyond these analyses of normal and diseased tissues, more recent reports have shown that miR species can be detected in the circulation [18] and suggested that analysis of serum samples for defined miR species could be used to identify patients with cancers [19,20,21,22,23,24,25] as well as other diseases such as cardiac disease [26,27,28,29,30] or diabetes mellitus [31]. Treatments will likely impact miR patterns in the circulation and these patterns may well be useful in establishing signatures of drug effects
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