SMAD1 as a biomarker and potential therapeutic target in drug-resistant multiple myeloma
نویسندگان
چکیده
Abstract Background SMAD1, a central mediator in TGF-β signaling, is involved broad range of biological activities including cell growth, apoptosis, development and immune response, implicated diverse type malignancies. Whether SMAD1 plays an important role multiple myeloma (MM) pathogenesis can serve as therapeutic target are largely unknown. Methods Myeloma lines primary MM samples were used. Cell culture, cytotoxicity apoptosis assay, siRNA transfection, Western blot, RT-PCR, Soft-agar colony formation, migration Chromatin immunoprecipitation (Chip), animal xenograft model studies statistical analysis applied this study. Results We demonstrate that highly expressed cells patients with advanced stages or relapsed disease, associated significantly shorter progression-free overall survivals. Mechanistically, we show required for TGFβ-mediated proliferation via ID1/p21/p27 pathway. also enhanced TNFα-Induced protein 8 (TNFAIP8) expression inhibited through SMAD1-mediated induction NF-κB1. Accordingly, depletion led to downregulation NF-κB1 TNFAIP8, resulting caspase-8-induced apoptosis. In turn, inhibition suppressed ID1 uncovering autoregulatory loop. Dorsomorphin (DM), inhibitor, exerted dose-dependent cytotoxic effect on drug-resistant minimal normal hematopoietic cells, further synergized the proteasomal-inhibitor bortezomib effectively kill vitro model. Conclusions This study identifies regulation NF-κB1/TNFAIP8 ID1-p21/p27 critical axes drug resistance provides potentially new strategy treat targeted SMAD1.
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ژورنال
عنوان ژورنال: Biomarker research
سال: 2021
ISSN: ['2050-7771']
DOI: https://doi.org/10.1186/s40364-021-00296-7