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

miRNA;miR-26;miR-26a;miR-26b;tumorigenesis;colon cancer;hepatocellular carcinoma;colon;intestine;liver;post-transcriptional regulation;Human Genetics and Molecular Biology

Zeitels, Lauren RachelSmith, Kirby ;

Johns Hopkins University

关键词: miRNA;    miR-26;    miR-26a;    miR-26b;    tumorigenesis;    colon cancer;    hepatocellular carcinoma;    colon;    intestine;    liver;    post-transcriptional regulation;    Human Genetics and Molecular Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60515/Zeitels%20Thesis%20Format%20%286%29.pdf?sequence=2&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

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.