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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6
Akiyo Yoshida1,2, Shunsuke Kitajima1,3, Fengkai Li1
1Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
Abstract:
We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3'-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response.
Insights
Retinoblastoma (Rb) protein loss promotes aggressive tumor growth by altering microRNA expression. miR-140 counteracts this effect by downregulating IL-6, offering a potential therapeutic target for cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The retinoblastoma (Rb) protein is a critical tumor suppressor.
- Rb pathway inactivation is common in many cancers.
- Understanding Rb's role in tumor progression is vital for developing new therapies.
Purpose of the Study:
- To investigate novel activities of the Rb protein during tumor progression using an in vitro cell culture system.
- To identify microRNAs (miRNAs) associated with Rb status and tumor aggressiveness.
- To elucidate the regulatory mechanism of miR-140 in Rb-mediated tumor suppression.
Main Methods:
- Established an in vitro cell culture system using p53-null mouse soft tissue sarcoma cells.
- Depleted Rb protein to induce spherogenesis and analyzed cell behavior.
- Utilized miRNA profiling to identify differentially expressed miRNAs.
- Performed functional studies to assess the role of mmu-miR-140 in regulating spherogenesis and IL-6 expression.
- Validated findings in a human breast cancer cell line (MCF-7).
Main Results:
- Rb depletion induced a spherogenic phenotype with increased aggressiveness.
- Six miRNAs, including mmu-miR-140, showed correlation with Rb status and spherogenic activity.
- mmu-miR-140 positively regulated by Rb, antagonized Rb depletion effects on spherogenesis.
- Rb depletion upregulated IL-6, while mmu-miR-140 overexpression downregulated IL-6, targeting its 3'-untranslated region.
- The RB-miR-140-IL-6 axis was conserved in human breast cancer cells.
Conclusions:
- Rb protein influences tumor progression partly through regulating specific miRNAs.
- mmu-miR-140 acts as a tumor suppressor by downregulating IL-6, mediated by Rb.
- The identified RB-miR-140-IL-6 pathway represents a potential therapeutic target in cancers with RB pathway inactivation.
- hsa-miR-140 may serve as a therapeutic tool to disrupt the link between tumor suppressor inactivation and pro-inflammatory cytokine response.
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