TY - JOUR AU - Mahdloo, Touba AU - Sahami, Pantea AU - Ramezani, Reihaneh AU - Jafarinia, Mojtaba AU - Goudarzi, Hamedreza AU - Babashah, Sadegh PY - 2021/04/15 Y2 - 2024/03/29 TI - Up-regulation of miR-155 potentiates CD34+ CML stem/progenitor cells to escape from the growth-inhibitory effects of TGF-β1 and BMP signaling JF - EXCLI Journal JA - EXCLI J. VL - 20 IS - SE - Original articles DO - 10.17179/excli2021-3404 UR - https://www.excli.de/index.php/excli/article/view/3404 SP - 748-763 AB - <p>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<sup>+</sup> CML cells to escape from the growth-inhibitory effects of TGF-β1 and bone morphogenetic protein (BMP) signaling. Among differentially expressed miRNAs in CD34<sup>+</sup> 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<sup>+</sup> CML cells. Results showed that siRNA-mediated knockdown of SMAD5 had a promoting effect on CD34<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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.</p> ER -