Up-regulation of miR-155 potentiates CD34+ CML stem/progenitor cells to escape from the growth-inhibitory effects of TGF-β1 and BMP signaling

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Touba Mahdloo
Pantea Sahami
Reihaneh Ramezani
Mojtaba Jafarinia
Hamedreza Goudarzi
Sadegh Babashah

Abstract

microRNAs (miRNAs or miRs) play key roles in different stages of chronic myeloid leukemia (CML) pathogenesis. The present study aimed to demonstrate whether miR-155 enables CD34+ CML cells to escape from the growth-inhibitory effects of TGF-β1 and bone morphogenetic protein (BMP) signaling. Among differentially expressed miRNAs in CD34+ CML cells, miR-155 was highly up-regulated. QRT-PCR revealed an inverse correlation between miR-155 and two key members of the TGF-β pathway—TGF-βR2 and SMAD5. Results showed that SMAD5 is not only up-regulated through BMPs treatment, but recombinant TGF-β1 can also induce SMAD5 in CML cells. We also demonstrated that TGF-β1-mediated phosphorylation of SMAD1/5 was abolished by pre-treatment with the blocking TGF-βR2 antibody, suggesting a possible involvement of TGF-βR2. Additionally, overexpression of miR-155 significantly promoted the proliferation rate of CD34+ CML cells. Results showed that siRNA-mediated knockdown of SMAD5 had a promoting effect on CD34+ CML cell proliferation, suggesting that SMAD5 knock-down recapitulates the proliferative effects of miR-155. Importantly, TGF-β1 and BMP2/4 treatment had inhibitory effects on cell proliferation; however, miR-155 overexpression enabled CD34+ CML cells to evade the anti-proliferative effects of TGF-β1 and BMPs. Consistently, down-regulation of miR-155 augmented the promoting effects of TGF-β1 and BMP signaling on inducing apoptosis in CD34+ CML stem cells. Our findings demonstrated that targeting of SMAD5 and TGF-βR2 links miR-155 to TGF-β signaling in CML. Overexpression of miR-155 enables CD34+ CML cells to evade growth-inhibitory effects of the TGF-β1 and BMP signaling, providing new perspectives for miR-155 as a therapeutic target for CML.

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How to Cite
Mahdloo, T., Sahami, P., Ramezani, R. ., Jafarinia, M. ., Goudarzi, H., & Babashah, S. (2021). Up-regulation of miR-155 potentiates CD34+ CML stem/progenitor cells to escape from the growth-inhibitory effects of TGF-β1 and BMP signaling. EXCLI Journal, 20, 748-763. https://doi.org/10.17179/excli2021-3404
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Original articles