MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

Abstract

Increased activity of MYC protein-family members is a common feature in many cancers. Using neuroblastoma as a tumor model, we established a microRNA (miRNA) signature for activated MYCN/c-MYC signaling in two independent primary neuroblastoma tumor cohorts and provide evidence that c-MYC and MYCN have overlapping functions. On the basis of an integrated approach including miRNA and messenger RNA (mRNA) gene expression data we show that miRNA activation contributes to widespread mRNA repression, both in c-MYCand MYCN-activated tumors. c-MYC/MYCN-induced miRNA activation was shown to be dependent on c-MYC/ MYCN promoter binding as evidenced by chromatin immunoprecipitation. Finally, we show that pathways, repressed through c-MYC/MYCN miRNA activation, are highly correlated to tumor aggressiveness and are conserved across different tumor entities suggesting that c-MYC/ MYCN activate a core set of miRNAs for cooperative repression of common transcriptional programs related to disease aggressiveness. Our results uncover a widespread correlation between miRNA activation and c-MYC/ MYCN-mediated coding gene expression modulation and further substantiate the overlapping functions of c-MYC and MYCN in the process of tumorigenesis.

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…MiR-9 has also been found to sensitize cells to EMT-inducing signals arising from the TME [129]. Overall, the c-myc-induced miRNA network is reported to be directly related to tumor aggressiveness in various types of cancers [130].…”

Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein

“…It is not fully established how MYCBP regulates these E-box-containing genes because of growing evidence about the function of MYCBP (Furusawa et al, 2001Yukitake et al, 2002;Ishizaki et al, 2006), but there is evidence suggesting that MYCBP acts, at least in part, through modulating the transactivation activity of c-Myc to enhance the transcription of these genes (Taira et al, 1998;Sakamuro and Prendergast, 1999). Recent studies showed that some c-Myc-mediated miRNAs were implicated in tumorigenesis, embryonic stem cell differentiation and glutamine metabolism (He et al, 2005;O'Donnell et al, 2005;Dews et al, 2006;Chang et al, 2008;Sander et al, 2008;Gao et al, 2009;Lin et al, 2009;Mestdagh et al, 2009). However, only two miRNAs were found to modulate c-Myc, whereas c-Myc is not their significant targets (Sampson et al, 2007;Lal et al, 2009).…”

“…The MYCBP (AMY-1) gene encodes a small c-Mycbinding protein of B11 kD, that binds the N-terminal domain of c-Myc through its C-terminal region and stimulates E-box-dependent transcriptional activation of c-Myc to promote tumorigenesis (Taira et al, 1998;Sakamuro and Prendergast, 1999). Several miRNAs have been found to regulate cell proliferation and anchorage-dependent growth (Esquela-Kerscher and Slack, 2006), but cross-talk between miRNAs and Myc genes has only started to emerge (Chang et al, 2008;Mestdagh et al, 2009). In this respect, recent studies have shown that c-Myc acts directly as a regulator of a broad panel of miRNAs including miR-22 (Chang et al, 2008;Mestdagh et al, 2009), but the effects of miRNAs on c-Myc expression and function are largely unknown.…”

“…Several miRNAs have been found to regulate cell proliferation and anchorage-dependent growth (Esquela-Kerscher and Slack, 2006), but cross-talk between miRNAs and Myc genes has only started to emerge (Chang et al, 2008;Mestdagh et al, 2009). In this respect, recent studies have shown that c-Myc acts directly as a regulator of a broad panel of miRNAs including miR-22 (Chang et al, 2008;Mestdagh et al, 2009), but the effects of miRNAs on c-Myc expression and function are largely unknown.…”

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

“…[1][2][3][4] Various miRNAs are overexpressed or underexpressed in different types of cancer in humans and may function as either tumor suppressors or oncogenes. [5][6][7][8][9][10][11][12][13] A cluster of six miRNAs (miR-17-92, comprising miR-17, miR18a, miR-20a, miR-19a, miR-19b-1, and miR-92a-1) is processed from the transcript of C13orf25 (also known as MIR17HG or MIRHG1), a gene amplified in some lymphomas and solid tumors 5,14 -17 and overexpressed in a large fraction of lymphomas. 5 Overexpression of miR-17-92 accelerates lymphomagenesis in mouse models.…”