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Updated: Apr 22, 2026
Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
Published on: June 15, 2016
A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies
M Ortega1, H Bhatnagar1, A-P Lin1
1Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Abstract:
Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de-repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC.
Insights
MicroRNA-30a (miR-30a) forms a feedback loop with MYC and NOTCH signaling, impacting lymphoid malignancies. This loop shows miR-30a has a tumor-suppressive role in diffuse large B-cell lymphoma and T-acute lymphoblastic leukemia.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression, influencing cellular processes.
- MYC and NOTCH signaling pathways are implicated in the development of lymphoid cancers.
- The interplay between MYC, NOTCH, and miRNAs in cancer pathogenesis is an area of active research.
Purpose of the Study:
- To investigate the regulatory relationship between MYC, NOTCH, and microRNA-30a (miR-30a).
- To determine the role of the miR-30a-NOTCH-MYC circuitry in lymphoid malignancies.
- To explore the potential of targeting this circuitry for therapeutic strategies.
Main Methods:
- Utilized murine models and genetically modified human cell lines.
- Employed genetic modulation and pharmacological inhibition techniques.
- Analyzed primary samples from diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) patients.
Main Results:
- Demonstrated a bidirectional regulatory loop where MYC suppresses miR-30a, which in turn inhibits NOTCH1/2.
- Showed that NOTCH1/2 signaling induces MYC, leading to suppression of miR-30a.
- Confirmed a tumor-suppressive function of miR-30a in DLBCL and T-ALL models.
- Validated the miR-30a-NOTCH-MYC loop activity in primary cancer samples.
Conclusions:
- Established a novel miRNA-mediated regulatory circuit involving miR-30a, MYC, and NOTCH.
- Highlighted the significance of this circuitry in modulating oncogenic signaling in lymphoid malignancies.
- Suggests that the miR-30a-NOTCH-MYC axis represents a potential therapeutic target.
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