Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.
BackgroundDysregulated microRNA (miRNA) expression contributes to cancer cell proliferation, apoptosis and angiogenesis. Angiogenesis is a hallmark of multiple myeloma (MM) development and progression. Argonaute 2 (AGO2) protein, a core component of the RNA-induced silencing complex (RISC), can directly bind to miRNAs and mediate target messenger RNA (mRNA) degradation. A previous study showed that AGO2 knockdown suppressed human umbilical vein endothelial cell (HUVEC) growth and tube formation. However, the roles and molecular mechanisms of AGO2-induced myeloma angiogenesis are not yet fully understood. The aim of this study was to characterize these roles and effects and their associated mechanisms.ResultsSupernatants from AGO2-overexpressing MM lines induced HUVEC migration and accelerated tube formation. Conversely, supernatants from AGO2-knockdown MM lines suppressed HUVEC cell migration and tube formation. Moreover, a chick chorioallantoic membrane (CAM) assay was used to demonstrate that AGO2 could drive neovessel formation in MM lines in vivo. Using an miRNA microarray, we observed that 25 miRNAs were upregulated and 7 were downregulated in response to AGO2. Most let-7 family members and 2 miR-17/92 cluster members (miR-17a and miR-92-1), all known pro-angiogenic miRNAs, were positively regulated by AGO2 whereas anti-angiogenic miRNAs such as miR-145 and miR-361 were negatively regulated by AGO2.ConclusionsWe conclude that AGO2 can drive neovessel formation in vitro and in vivo by dysregulating the expression of some angiogenic miRNAs. The pro-angiogenic miRNAs of the let-7 family and the miR-17/92 cluster, along with the anti-angiogenic miRNA miR-145, play crucial roles in AGO2-mediated angiogenesis by targeting angiogenesis-related genes.
The ring-opening polymerization (ROP) of trimethylene carbonate (TMC) using a base-acid binary organocatalyst system of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) and Brønsted acid trifluoromethanesulfonic acid (TFA) with benzyl alcohol (BnOH) as the initiator has been investigated. The MTBD and its conjugate-acid pair H-bonding bifunctional synergistic activation mechanism was demonstrated by NMR measurements, and the living/controlled nature of MTBD/TFA catalyzed ROP of TMC was confirmed by the kinetic and chain extension experiments. The controlled ROP of TMC with the optimal molar ratio of MTBD/TFA = 2/1 proceeded to afford well-defined PTMC with narrow molecular weight distributions (M w /M n ∼ 1.1). The molecular weights determined by 1 H NMR are in precise agreement with the theoretical values. 1 H NMR, SEC, and MALDI-ToF MS measurements confirmed the structure of the obtained homopolymer PTMC. In addition, a diblock copolymer consisting of poly(trimethylene carbonate) and poly(L-lactide) (PTMC-b-PLLA) was synthesized successfully by the MTBD/TFA binary catalyst system.
Aluminum substituted barium hexaferrites were prepared by the self-propagating combustion method and subsequent calcination at 850 °C. The crystalline structure, complex permittivity, complex permeability, and hyperfine parameters of BaFe12−xAlxO19 (x varies from 1.5 to 2.3 in steps of 0.2) were measured with x-ray diffraction (XRD), vector network analyzer and Mössbauer spectroscopy. The XRD results show that all Al3+ ions enter into the lattice of hexagonal barium ferrite. The substitution of Al3+ ions can greatly affect the complex permittivity and permeability of barium ferrite. With increasing substitution, the real part of complex permittivity increases gradually, and the peaks of the imaginary part of complex permeability shift into higher frequency band. When the substitution amount x is 1.9, the largest movement of the peaks is 1.95 GHz, which indicates that the ferromagnetic resonant frequency of barium ferrite increases by 1.95 GHz. The Al3+ ions preferentially occupy the 4f2, 2a, 4f1, and 12k sites in the subcrystalline structure up to x=1.9, and then the Al3+ ions mainly occupy 12k sites. This change also results in 2b sites with a large quadrupole splitting. These occupations lead to a variable magnetocrystalline anisotropy field.
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