scholarly journals Potential role of exosome-associated microRNA panels and in vivo environment to predict drug resistance for patients with multiple myeloma

Oncotarget ◽  
2016 ◽  
Vol 7 (21) ◽  
pp. 30876-30891 ◽  
Author(s):  
Li Zhang ◽  
Ling Pan ◽  
Bing Xiang ◽  
Huanling Zhu ◽  
Yu Wu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Potential Role

HOXB7 Is Critically Involved in Multiple Myeloma-Induced Angiogenic Switch.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 125-125
Author(s):  
Paola Storti ◽  
Gaetano Donofrio ◽  
Marina Bolzoni ◽  
Simona Colla ◽  
Irma Airoldi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Protein Level ◽  
Potential Role ◽  
Tumor Mass ◽  
Angiogenic Switch ◽  
Angiogenic Inhibitor

Abstract Abstract 125 It is known that bone marrow (BM) angiogenesis is increased in multiple myeloma (MM) patients in relationship with disease progression and supports MM cell growth. MM-induced angiogenesis is mainly due to an overproduction of pro-angiogenic molecules by MM cells and the BM microenvironment. However, the molecular mechanisms at the basis of the angiogenic process are currently under investigation. The deregulation of the homeobox genes has been previously associated to tumor progression and neoangiogenesis. Particularly, overexpression of the homeobox HOXB7 is involved in tumor-associated angiogenic switch in solid tumors. Interestingly, we have recently shown that HOXB7 is one of the overexpressed genes in BM micorenvironment cells in MM patients as compared to healthy subjects. In this study we have investigated the expression of HOXB7 by MM cells and its potential role in MM-induced angiogenesis in vitro and in vivo. First, by microarray analysis we evaluated HOXB7 expression in MM cells finding that HOXB7 was overexpressed in 43% of 23 human myeloma cell lines (HMCLs) tested as compared to normal plasmacells. HOXB7 expression was further confirmed by real time PCR and western blot analysis. On the other hand a small fraction of patients (about 10% in a representative database of 133 MM patients) showed HOXB7 overexpression with a preferential distribution based on the characteristics of molecular MM subtypes being significantly overexpressed in those cases which did not show any of the primary IGH translocations, corresponding to the TC2 and TC3 groups in the translocations/cyclins (TC) classification. In order to investigate the potential role of HOXB7 in MM cells either we enforced HOXB7 expression by lentivirus vectors in JJN3 HMCL (JJN3-HOXB7) or we silenced its expression by appropriate siRNA in the KMS20 HMCL that constitutively over-expressed HOXB7. Interestingly we found that cell proliferation was significant higher in JJN3-HOXB7 as compared to JJN3 transduced with the empty vector (JJN3-pWPI) as well as HOXB7 downregulation in KMS20 significantly reduced their cell proliferation and viability. Following we evaluated the whole transcriptional and specifically the pro-angiogenic profile of JJN3-HOXB7 as compared to JJN3-pWPI using Genechips® HG-U133Plus 2.0 and an angiogenesis oligonucleotide arrays. We found that the pro-angiogenic cytokines as VEGFA, FGF2, MMP2 and PDGFA were significantly upregulated whereas we identified the specific downregulation of the angiogenic inhibitor TSP2 in JJN3-HOXB7. Data were then validated at protein level by ELISA assay in cell-conditioned media (CM). Consistently, we found that CM of JJN3-HOXB7 significantly stimulated vessel formation as compared to JJN3-pWPI using both in vitro angiogenic model (Angiokit) and chorioallantoic membrane assay. In line with these observations, we found that HOXB7 silencing by siRNA in KMS20 reduced the expression of pro-angiogenic molecules, including VEGF and FGF2, and growth factors. Finally the potential role of HOXB7 in MM-induced angiogenesis was tested in vivo in NOD/SCID mice. We found that mice injected with JJN3-HOXB7 cells developed a significantly bigger tumor mass than mice inoculated with the JJN3-pWPI (p=0.0039) with higher number of vessels stained by CD31 antigen. Moreover, the transcriptional and angiogenic profiles of the tumor mass indicated the upregulation of VEGFA, FGF2, MMP2, PDGFA and WNT5a as well as the downregulation of TSP2, at both mRNA and protein level in mice colonized by JJN3-HOXB7 as compared to those inoculated with JJN3-pWPI, confirming in vitro observations. In conclusion our data demonstrate the critical role of HOXB7 in the production of pro-angiogenic molecules by MM cells and in the regulation of MM-induced angiogenic switch suggesting that HOXB7 could be a potential therapeutic target in MM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment 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.

scholarly journals PIWIL1 Drives Chemoresistance in Multiple Myeloma by Modulating Mitophagy and the Myeloma Stem Cell Population

2022 ◽  
Vol 11 ◽  
Author(s):  
Yajun Wang ◽  
Lan Yao ◽  
Yao Teng ◽  
Hua Yin ◽  
Qiuling Wu
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cell Population ◽  
Side Population ◽  
Chemotherapeutic Agents ◽  
Stem Cell Population ◽  
Exact Function

As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.

scholarly journals HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Fengjie Jiang ◽  
Xiaozhu Tang ◽  
Chao Tang ◽  
Zhen Hua ◽  
Mengying Ke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Aberrant Expression ◽  
The Stability ◽  
Induced Apoptosis ◽  
Proliferation In Vitro

AbstractN6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic RNAs while accumulating studies suggest that m6A aberrant expression plays an important role in cancer. HNRNPA2B1 is a m6A reader which binds to nascent RNA and thus affects a perplexing array of RNA metabolism exquisitely. Despite unveiled facets that HNRNPA2B1 is deregulated in several tumors and facilitates tumor growth, a clear role of HNRNPA2B1 in multiple myeloma (MM) remains elusive. Herein, we analyzed the function and the regulatory mechanism of HNRNPA2B1 in MM. We found that HNRNPA2B1 was elevated in MM patients and negatively correlated with favorable prognosis. The depletion of HNRNPA2B1 in MM cells inhibited cell proliferation and induced apoptosis. On the contrary, the overexpression of HNRNPA2B1 promoted cell proliferation in vitro and in vivo. Mechanistic studies revealed that HNRNPA2B1 recognized the m6A sites of ILF3 and enhanced the stability of ILF3 mRNA transcripts, while AKT3 downregulation by siRNA abrogated the cellular proliferation induced by HNRNPA2B1 overexpression. Additionally, the expression of HNRNPA2B1, ILF3 and AKT3 was positively associated with each other in MM tissues tested by immunohistochemistry. In summary, our study highlights that HNRNPA2B1 potentially acts as a therapeutic target of MM through regulating AKT3 expression mediated by ILF3-dependent pattern.

The potential role of miRNAs in multiple myeloma therapy

2018 ◽  
Vol 11 (10) ◽  
pp. 793-803 ◽  
Author(s):  
Daniele Caracciolo ◽  
Martina Montesano ◽  
Emanuela Altomare ◽  
Francesca Scionti ◽  
Maria Teresa Di Martino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Potential Role

scholarly journals Decreased MiR-128-3p alleviates the progression of rheumatoid arthritis by up-regulating the expression of TNFAIP3

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Zhongbin Xia ◽  
Fanru Meng ◽  
Ying Liu ◽  
Yuxuan Fang ◽  
Xia Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Peripheral Blood ◽  
Potential Role ◽  
Enzyme Linked Immunosorbent Assay ◽  
Normal Person ◽  
Synovial Joint ◽  
Peripheral Blood Mononuclear

Background: Rheumatoid arthritis (RA) is a inflammatory disease that characterized with the destruction of synovial joint, which could induce disability. Inflammatory response mediated the RA. It has been reported that MiR-128-3p is significantly increased in RA, while the potential role was still unclear. Methods: T cells in peripheral blood mononuclear cell (PBMC) were isolated from the peripheral blood from people of RA and normal person were used. Real-time PCR was performed to detect the expression of MiR-128-3p, while the protein expression of tumor necrosis factor-α-induced protein 3 (TNFAIP3) was determined using Western blot. The levels of IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA). The expression of CD69 and CD25 was detected using flow cytometry. The RA mouse model was constructed for verification of the role of MiR-128-3p. Results: The expression of MiR-128-3p was significantly increased, while TNFAIP3 was decreased, the levels of IL-6 and IL-17 were also increased in the T cells of RA patients. Down-regulated MiR-128-3p significantly suppressed the expression of p-IkBα and CD69, and CD25in T cells. MiR-128-3p targets TNFAIP3 to regulate its expression. MiR-128-3p knockdown significantly suppressed the activity of nuclear factor κB (NF-κB) and T cells by up-regulating TNFAIP3, while cells co-transfected with si-TNFAIP3 abolished the effects of MiR-128-3p knockdown. The in vivo experiments verified the potential role of MiR-128-3p on RA. Conclusion: Down-regulated MiR-128-3p significantly suppressed the inflammation response of RA through suppressing the activity of NF-κB pathway, which was mediated by TNFAIP3.

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