Abstract
Let-7 miRNAs comprise one of the largest and most highly expressed family of miRNAs among vertebrates, and is critical for promoting differentiation, regulating metabolism, inhibiting cellular proliferation, and repressing carcinogenesis in a variety of tissues. The large size of the Let-7 family of miRNAs has complicated the development of mutant animal models. Here we describe the comprehensive repression of all Let-7 miRNAs in the intestinal epithelium via low-level tissue-specific expression of the Lin28b RNA-binding protein and a conditional knockout of the MirLet7c-2/Mirlet7b locus. This ablation of Let-7 triggers the development of intestinal adenocarcinomas concomitant with reduced survival. Analysis of both mouse and human intestinal cancer specimens reveals that stem cell markers were significantly associated with loss of Let-7 miRNA expression, and that a number of Let-7 targets were elevated, including Hmga1 and Hmga2. Functional studies in 3-D enteroids revealed that Hmga2 is necessary and sufficient to mediate many characteristics of Let-7 depletion, namely accelerating cell cycle progression and enhancing a stem cell phenotype. In addition, inactivation of a single Hmga2 allele in the mouse intestine epithelium significantly represses tumorigenesis driven by Lin28b. In aggregate, we conclude that Let-7 depletion drives a stem cell phenotype and the development of intestinal cancer, primarily via Hmga2.
Highlights
Micro-RNAs are critical for tumor suppression, which is most notably revealed following genetic manipulation of Dicer1, an enzyme needed for miRNA processing, in which haplo-insufficiency of Dicer1 and global reduction of miRNA levels significantly accelerates tumorigenesis [1,2]
Our further analysis identified another gene, HMGA2, downstream of this pathway that is critical to this outcome
We have demonstrated that LIN28B is a potent driver of colorectal cancer (CRC) progression, cellular invasion, and in mouse models, a regulator of intestinal growth and tumorigenesis [15,18,30]
Summary
Micro-RNAs (miRNAs) are critical for tumor suppression, which is most notably revealed following genetic manipulation of Dicer, an enzyme needed for miRNA processing, in which haplo-insufficiency of Dicer and global reduction of miRNA levels significantly accelerates tumorigenesis [1,2]. Let-7 miRNAs comprise one of the largest and most highly expressed families of miRNAs, possessing potent anti-carcinogenic properties in a variety of tissues [3]. This activity is likely mediated via Let-7 repression of a multitude of onco-fetal mRNAs and other pro-proliferative and/or pro-metastatic targets, such as HMGA2, IGF2BP1, IGF2BP2, and NR6A1 [4,5,6]. The critical nature of maintaining sufficient levels of mature Let-7 miRNAs is reflected in the large number of studies that have found LIN28A or LIN28B up-regulated in human cancers, with expression often associated with an aggressive disease phenotype and/or predictive of poor outcomes [12,13,14,15]. LIN28B appears somewhat more frequently up-regulated than LIN28A in cancer, and may reflect the greater expression potential of LIN28B in adult tissues: LIN28B exhibits a later temporal pattern of expression in adult tissues such as the intestine, plays a greater role in post-natal growth, and can be re-activated by inflammation and NF-kappa-B [16,17,18,19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
