miR-19 is a key oncogenic component of mir-17-92

Abstract

Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Em-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt-mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis.

MiR‐17~92 ablation impairs liver regeneration in an estrogen‐dependent manner

“…5A). Luciferase reporter gene assay confirmed that the miR‐17~92 cluster directly targets the 3′UTRs of the Pten and p21 genes, as shown in Figure 5B and C in accordance with previous reports 17, 27. Our immunoblotting results revealed that the loss of miR‐17~92 caused slight changes in the levels of cyclin D1, Pten and p21 levels in the male mice (Fig.…”

Dietary Manipulation of Oncogenic MicroRNA Expression in Human Rectal Mucosa: A Randomized Trial

“…Elevated miR17-92 levels have been associated with invasion and metastasis of colorectal cancer cells (32), and poorer survival (33). miR19a and miR19b in particular are key oncogenic determinants (29,30), and both were significantly elevated with the HRM diet compared with the entry diet. miR21 has similarly been classed as oncogenic, and can also induce tumorigenesis, invasion, and metastasis (34)(35)(36).…”

“…HRM intake significantly increased rectal mucosa levels of miR17-92 cluster miRNAs and miR21, which are both elevated in colorectal cancer (16,17). The miR17-92 cluster has been designated oncomir-1 (31), and can promote proliferation and angiogenesis, inhibit differentiation, and sustain cell survival (29,30). Elevated miR17-92 levels have been associated with invasion and metastasis of colorectal cancer cells (32), and poorer survival (33).…”

“…[27][28][29][30]. The influence of the diet-induced changes in miR17-92 cluster miRNA levels on these target genes was investigated in the rectal biopsy samples.…”

The emerging role of miR‐19 in glioma

“…MiR‐19 promotes tumourigenesis by regulating target genes and related signalling pathways. In human B‐cell lymphomas, miR‐19 promotes tumour cell survival by inhibiting PTEN directly and activating AKT/mTOR pathway 22. Expression of miR‐19 is elevated in SHH medulloblastoma, a subgroup of medulloblastoma characeterized as constitutive activation of the Sonic Hedgehog pathway, anti‐miR‐19 treatment restrains proliferation of tumour cells and prolongs survival of tumour‐bearing mice23 (Figure 1).…”