miR-17-92 cluster components analysis in Burkitt lymphoma: overexpression of miR-17 is associated with poor prognosis

Abstract

Burkitt lymphoma (BL) is an aggressive B cell lymphoma characterized by the reciprocal translocation of the c-Myc gene with immunoglobulin genes. Recently, MYC has been shown to maintain the neoplastic state via the miR-17-92 microRNA cluster that suppresses chromatin regulatory genes and the apoptosis regulator Bim. However, the expression and prognostic impact of miR-17-92 members in pediatric BL (pBL) are unknown. Therefore, we investigated miR-17, miR-19a, miR-19b, miR-20, and miR-92a expression and prognostic impact in a series of 41 pBL samples. In addition, Bim protein expression was evaluated and compared to miR-17, miR-19a, miR-19b, miR-20, and miR-92a levels and patient outcomes. The expression of miR-17-92 members was evaluated by qPCR and Bim protein by immunohistochemistry. Log-rank test was employed to assess prognostic impact. We found that upregulated expression of miR-17 and miR-20a correlates with lack of pro-apoptotic Bim expression. Patients bearing tumors with upregulated miR-17 displayed decreased overall survival (OS), and multivariate analysis revealed that miR-17 was a significant predictor of shortened OS. Using hairpin inhibitors, we showed that inhibition of miR-17 resulted in enhanced Bim expression in a BL cell line overexpressing the miR-17-92 cluster. Our results describe for the first time miR-17, miR-19a, miR-19b, miR-20a, and miR-92a expression profiles in pBL. The prognostic impact of miR-17 should be validated in a larger series, and may provide new therapeutic avenues in the era of anti-miRNA therapy research. Additional functional studies are further required to understand the specific role of miR-17-92 cluster members in BL.

Oncogenic miR-19a and miR-19b co-regulate tumor suppressor MTUS1 to promote cell proliferation and migration in lung cancer

“…Downregulation of tumor-suppressor miRNAs (targeting oncogenes) and upregulation of oncogenic miRNAs (targeting tumor suppressor genes) lead to cancer cell dysfunction, including malignant proliferation, invasion, and metastasis (Calin and Croce, 2006; Ma and Weinberg, 2008; Nicoloso et al, 2009). The miR-17-92 miRNA cluster is one of the best characterized groups of miRNA oncogenes, and genomic amplification or aberrant expression of these miRNAs is frequently observed in a variety of tumor types (Olive et al, 2013; Guinot et al, 2016; Robaina et al, 2016). As members of the miR-17-92 cluster, miR-19a and miR-19b (miR-19a/b) usually function as oncogenes in many types of cancer, including gastric cancer (Lu et al, 2015), pancreatic cancer (Wang et al, 2016), and breast cancer (Li et al, 2014b).…”

Clustered miRNAs and their role in biological functions and diseases

“…(5) miRNA clusters and resistance to apoptosis miRNA clusters target many protein-coding genes involved in apoptotic pathways (Robaina et al, 2016;Su et al, 2016). For instance, miR-17/92 cluster in the presence of activated c-Myc has shown to inhibit apoptosis by preventing excessive E2F1 activity.…”

“…Bonci et al (2008) showed that CCND1 and WNT3A are targets of this cluster and forced expression induced growth arrest and apoptosis. Anti-apoptotic genes (BCL-2, Activin A and CCND1) (Bonci et al, 2008;Li et al, 2013a;Bufalino et al, 2015) and pro-apoptotic genes (p53, BIM and Caspase-7) (Tang et al, 2013;Balatti et al, 2016;Robaina et al, 2016) are often targets of miRNA clusters and are important for inhibiting apoptosis. miR-106b/25 is significantly upregulated in prostate cancer and shows resistance to apoptosis by targeting CASP7 (Hudson et al, 2013).…”

The emerging role of miR‐19 in glioma

“…The target genes of miR‐17‐92 cluster have been experimentally identified so far including: STAT3, Mapk1410 and Rb2/p130 11. MiR‐17‐92 cluster plays an important role in tumourigenesis of thyroid cancer, leukaemia and lymphoma 12, 13, 14. The expression of miR‐17‐92 cluster is up‐regulated in glioma tissues.…”

“…11 MiR-17-92 cluster plays an important role in tumourigenesis of thyroid cancer, leukaemia and lymphoma. [12][13][14] The expression of miR-17-92 cluster is up-regulated in glioma tissues. MiR-17-92 cluster inhibition decreases cell proliferation and induces apoptosis in glioblastoma spheroids culture by upregulating the expression of CDKN1A (cyclin-dependent kinase inhibitor 1A), E2F1 and PTEN.…”