The Regulation and Function of miR-26 in Normal Physiology and Tumorigenesis

It has become increasingly clear that the dysregulation of microRNAs (miRNAs), small (18-21nt) noncoding RNAs, plays an integral role in both normal physiology and disease. Downregulation of miR-26 family members has been implicated in many settings of cellular proliferation including embryogenesis, regeneration, and malignancy. The work described herein further elucidates the regulation and role of miR-26 in normal physiology and disease. miRNAs biogenesis encompasses a series of processing steps, each of which can be individually regulated. We demonstrated that while repression of miR-26 in the regenerating liver occurs transcriptionally, downregulation of miR-26 in mouse embryonic liver, murine hepatocellular carcinoma, and human hepatocellular carcinoma cell lines occurs post-transcriptionally. The post-transcriptional regulation of miR-26 is mediated through either moderation of Dicer efficiency or mature miR-26 stability. These data identify a novel mechanism of miR-26 regulation and a potential pathway for therapeutic targeting. Downregulation of miR-26 family members has been implicated in the pathogenesis of multiple malignancies. In some settings including glioma, however, miR-26-mediated repression of PTEN promotes tumorigenesis. To investigate the contexts in which the tumor suppressor versus oncogenic activity of miR-26 predominates in vivo, we generated tet- and Cre-inducible miR-26a transgenic mice. Broad miR-26a expression was well tolerated, resulting only in a lactation deficiency. Despite measureable repression of Pten, elevated miR-26a levels were not associated with malignancy in transgenic animals. We documented reduced miR-26 expression in human colorectal cancer and accordingly showed that miR-26a expression potently suppressed intestinal adenoma formation in Apcmin/+ mice, a model known to be sensitive to Pten dosage. These studies reveal a tumor suppressive role for miR-26 in intestinal cancer that overrides putative oncogenic activity and highlight the therapeutic potential of miR-26 delivery to this and other tumor types