scholarly journals The Notch Target Genes Hey1 and Hes7 Transcriptionally Suppress Gli1 Expression and Hedgehog Signaling in Hodgkin-Reed/Sternberg Cells of Classical Hodgkin Lymphoma: A Novel Mechanism of Drug Resistance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 275-275
Author(s):  
Rolf Schwarzer ◽  
Julia Godau ◽  
Hermann Einsele ◽  
Franziska Jundt
Keyword(s):  
Drug Resistance ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Hodgkin Lymphoma ◽  
Target Genes ◽  
Classical Hodgkin Lymphoma ◽  
Notch Inhibition ◽  
Hh Signaling

Abstract Tumor cell proliferation and survival of Hodgkin/Reed-Sternberg (HRS) cells are triggered through Jagged1 ligand-induced Notch1 signaling via homotypic and heterotypic cell-cell interactions in classical Hodgkin lymphoma. The developmental pathway Notch partly mediates its effects in HRS cells by stimulation of alternative NF-kB signaling. We further demonstrated that high-level expression of the essential Notch coactivator Mastermind-like 2 and downregulation of the Notch inhibitor Deltex1 contribute to aberrant activation of Notch signaling in HRS cells. Our data suggested that targeting the Notch pathway is a rational treatment strategy in classical Hodgkin lymphoma. In this study we analyzed Notch inhibition by use of the gamma secretase inhibitor GSI XII in a Hodgkin lymphoma xenotransplantation model. To this end the HRS cell line L540cy (1 x 107 cells/per mouse) was transplanted into NOD/SCID mice. After tumor growth (0.3 cm³ mean tumor volume) mice were treated daily with increasing doses of GSI XII (5-10 mg/kg). Surprisingly, L540cy cells were completely drug-resistant in vivo in contrast to high GSI XII sensitivity in vitro. To dissect potential mechanisms of drug resistance we performed human StellARrayTM quantitative polymerase chain reaction (qPCR) arrays to analyze Notch target genes in GSI XII-treated compared to untreated L540cy cells. Interestingly, inhibition of Notch activity resulted in strong mRNA upregulation of the transcription factor glioma-associated oncogene 1 (Gli1), a final effector of the developmental signaling pathway Hedgehog (HH). Chromatin immunoprecipitation (ChIP) further revealed that both negative regulatory Notch target proteins Hey1 and Hes7 directly bind three different N-boxes present in the GLI1 first intron to suppress GLI1 mRNA expression in untreated L540cy cells. In general, the HH pathway is activated through ligand binding of secreted Sonic Hedgehog (SHH). As a result Gli transcription factors translocate to the nucleus and induce target gene expression such as GLI1 or CCND1. Despite high secretion of SHH by HRS cells after two days in culture (conditioned medium), HH signaling was inactive in untreated L540cy cells. Only after release of the negative regulatory Notch targets of the hairy and enhancer of split (HES) family through Notch inhibition and concomitant increase of Gli1 expression, HH signaling was activated by SHH. HH signaling mediated drug resistance of L540cy cells in conditioned medium compared to fresh medium (SHH negative) and thereby compensated for reduced Notch activity in vitro. We hypothesized that this mechanism might contribute to GSI XII drug resistance in vivo. To proof our hypothesis we coinhibited the Notch and HH pathways in L540cy cells. As expected inhibition of the HH pathway alone by use of cyclopamine did not significantly reduce growth of L540cy cells. However, simultaneous targeting of L540cy tumors through GSI XII and cyclopamine efficiently controlled tumor cell growth. Our data indicate a first molecular link between Notch and HH in HRS cells mediating drug resistance. We suggest inhibition of both developmental pathways for effective HRS tumor growth control. Disclosures No relevant conflicts of interest to declare.

scholarly journals Positive Crosstalk Between Hedgehog and NF-κB Pathways Is Dependent on KRAS Mutation in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuqiong Wang ◽  
Dan Wang ◽  
Yanmiao Dai ◽  
Xiangyu Kong ◽  
Xian Zhu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathways ◽  
Kras Mutation ◽  
Biological Effects ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Hh Signaling

It has been shown that aberrant activation of the Hedgehog (Hh) and nuclear factor-kappa B (NF-κB) signaling pathways plays an important role in the pancreatic carcinogenesis, and KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDAC). Until now, the role of KRAS mutation in the context of crosstalk between Hh and NF-κB signaling pathways in PDAC has not been investigated. This study was to determine whether the crosstalk between the Hh and NF-κB pathways is dependent on KRAS mutation in PDAC. The correlation between Gli1, Shh, NF-κB p65 expression and KRAS mutation in PDAC tissues was firstly examined by immunohistochemistry. Next, Western blotting, qPCR, and immunofluorescence were conducted to examine the biological effects of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) as NF-κB signaling agonists, Shh as an Hh ligand alone or in combination with KRAS small interfering RNA (si-KRAS) in KRAS-mutant PDAC cells (MT-KRAS; SW1990 and Panc-1), wild-type KRAS PDAC cells (WT-KRAS; BxPC-3) and mutant KRAS knock-in BxPC-3 cells in vitro as well as tumor growth in vivo. KRAS mutation-dependent crosstalk between Hh and NF-κB in PDAC cells was further assessed by Ras activity and luciferase reporter assays. The aberrant Hh and NF-κB pathway activation was found in PDAC tissues with KRAS mutation. The same findings were confirmed in MT-KRAS PDAC cells and MT-KRAS knock-in BxPC-3 cells, whereas this activation was not observed in WT-KRAS PDAC cells. However, the activation was significantly down-regulated by KRAS silencing in MT-KRAS PDAC cells. Furthermore, MT-KRAS cancer cell proliferation and survival in vitro and tumor growth after inoculation with MT-KRAS cells in vivo were promoted by NF-κB and Hh signaling activation. The pivotal factor for co-activation of NF-κB and Hh signaling is MT-KRAS protein upregulation, showing that positive crosstalk between Hh and NF-κB pathways is dependent upon KRAS mutation in PDAC.

scholarly journals Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ethan P. Metz ◽  
Erin L. Wuebben ◽  
Phillip J. Wilder ◽  
Jesse L. Cox ◽  
Kaustubh Datta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Cycle Machinery

Abstract Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

scholarly journals Maximal killing of lymphoma cells by DNA damage–inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5256-5267 ◽  
Author(s):  
Lina Happo ◽  
Mark S. Cragg ◽  
Belinda Phipson ◽  
Jon M. Haga ◽  
Elisa S. Jansen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Drug Resistance ◽  
Target Genes ◽  
B Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Lymphoid Cells ◽  
Lymphoma Cells ◽  
P53 Target Genes

Abstract DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eμ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eμ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eμ-Myc/Puma−/−Noxa−/− lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa−/−Puma−/−Bim−/− mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.

Thrombin Enhances Spontaneous Tumor Growth and Cell Cycle Activation by Downregulation of p27Kip1 and Upregulation of Skp2 and MiR-222

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 396-396
Author(s):  
Liang Hu ◽  
Sherif Ibrahim ◽  
Cynthia Liu ◽  
Jeffrey Skaar ◽  
Michelle Pagano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cell Growth ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Volume ◽  
S Phase ◽  
Down Regulation

Abstract Although it has been generally accepted that hypercoagulability contributes to enhancing tumor growth via generation of thrombin (Cancer Cell10:355, 2006), it has not been rigorously proven, nor has the mechanism been established at the cell cycle level. Previous studies have employed thrombin-treated tumor cell lines in vitro and in vivo. In vitro studies were performed in the presence of serum which contains a panoply of growth factors. In vivo studies have used huge non-pathologic concentrations of tumor cells injected into the flank, organ or blood of a mouse. In these situations, tumor growth could be a result of thrombin-induced angiogenesis. We therefore employed a transgenic mouse prostate cancer model (TRAMP) programmed to develop prostate CA over a period of 140–175 days. We treated these animals with thrombin to induce hypercoagulability or hirudin to inhibit endogenous thrombin production, to determine whether thrombin regulates this process independent of angiogenesis. Repetitive thrombin injection enhanced prostate tumor volume 6–8 fold (p<0.04). Repetitive hirudin decreased tumor volume 13–24 fold (p<0.04) via its effect on generated endogenous thrombin, n=6. Thrombin enhanced the production of several vascular growth factors and receptors 2.5 – 3 fold in the liver (VEGF, KDR, ANG-2, Tie2, GRO-1, CD31) and enhanced angiogenesis in the liver, n=3–4. Thrombin had no effect on tumor angiogenesis. Thus, the thrombin-induced spontaneous tumor growth was independent of angiogenesis. We next turned our attention to cell cycle regulators in serum-starved (72 hr) Go-synchronized LNcap prostate CA cells, employing Brdu and Propidium iodide staining. Addition of thrombin (0.5 u/ml) or its PAR-1 receptor agonist, TFLLRN (100 uM) had the same effect as androgen containing serum, inducing cells to leave Go, enter G1 and progress to S-phase. At 8 hrs the number of S-phase cells increased dramatically for both the serum (29 fold) as well as thrombin-treated cells (48 fold), n=3. Similar observations were noted in a Glioblastoma cell line, T98G. We further analyzed the effect of thrombin by performing immunoblots on cell cycle components mediated during cell growth and proliferation. In synchronized Go cells, levels of p27Kip1, a cyclin-dependent kinase inhibitor are high, while levels of cyclins D1 and A, the activation subunits for cyclin-dependent kinases are low. Both thrombin or serum addition led to down-regulation of p27Kip1 with concomitant induction of Skp2, the E3 ubiquitin ligase for p27Kip1. Cyclins D1 and A are induced by similar kinetics, indicating entry into S-phase by 8 hrs. Since p27Kip1 appears to be a rate-limiting down-regulator of the cell cycle (absent with high tumor grade and predicts poor prognosis), we confirmed its role by testing the effect of thrombin or TFLLRN by transfecting p27Kip1 in LNcap cells. This transfection completely prevented the cell cycle stimulation induced by these agonists. A similar approach was used with Skp2 knock down (KD), a negative down-regulator of p27Kip1. KD of Skp2 (over expressed in numerous cancers) completely prevented cell cycle progression induced by thrombin/TFLLRN. MiRNA 222 (upregulated in many cancers) is another down-regulator of p27Kip1. Further analysis following thrombin treatment revealed a robust upregulation at 4 and 8 hrs, providing further proof for the role of thrombin in down-regulating p27Kip1 and stimulating tumor cell entrance into S-phase. Thus, 1) Thrombin enhances spontaneous prostate cell growth in vivo in the absence of enhanced angiogenesis; 2) Thrombin activates the tumor cell cycle by stimulating the down-regulation of p27Kip1 through the upregulation of Skp2 and MiRNA 222.

scholarly journals TUSC1, a Putative Tumor Suppressor Gene, Reduces Tumor Cell Growth In Vitro and Tumor Growth In Vivo

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e66114 ◽  
Author(s):  
Zhihong Shan ◽  
Abbas Shakoori ◽  
Sohrab Bodaghi ◽  
Paul Goldsmith ◽  
Jen Jin ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Suppressor Gene ◽  
Tumor Cell Growth ◽  
Putative Tumor Suppressor Gene ◽  
Putative Tumor Suppressor

scholarly journals RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo

2017 ◽  
Vol 114 (8) ◽  
pp. E1413-E1421 ◽  
Author(s):  
Twana Alkasalias ◽  
Andrey Alexeyenko ◽  
Katharina Hennig ◽  
Frida Danielsson ◽  
Robert Jan Lebbink ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Rho Gtpase ◽  
Focal Adhesions ◽  
Cancer Associated Fibroblasts ◽  
Inhibitory Capacity ◽  
Promote Tumor Growth ◽  
Pc3 Cells

Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins overexpressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of α-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.

scholarly journals ASPP1 and ASPP2: Common Activators of p53 Family Members

2004 ◽  
Vol 24 (3) ◽  
pp. 1341-1350 ◽  
Author(s):  
Daniele Bergamaschi ◽  
Yardena Samuels ◽  
Boquan Jin ◽  
Sai Duraisingham ◽  
Tim Crook ◽  
...  
Keyword(s):  
Rna Interference ◽  
Tumor Growth ◽  
Target Genes ◽  
Family Members ◽  
Mutant P53 ◽  
P53 Family ◽  
P53 Target Genes

ABSTRACT We recently showed that ASPP1 and ASPP2 stimulate the apoptotic function of p53. We show here that ASPP1 and ASPP2 also induce apoptosis independently of p53. By binding to p63 and p73 in vitro and in vivo, ASPP1 and ASPP2 stimulate the transactivation function of p63 and p73 on the promoters of Bax, PIG3, and PUMA but not mdm2 or p21WAF-1/CIP1. The expression of ASPP1 and ASPP2 also enhances the apoptotic function of p63 and p73 by selectively inducing the expression of endogenous p53 target genes, such as PIG3 and PUMA, but not mdm2 or p21WAF-1/CIP1. Removal of endogenous p63 or p73 with RNA interference demonstrated that (16) the p53-independent apoptotic function of ASPP1 and ASPP2 is mediated mainly by p63 and p73. Hence, ASPP1 and ASPP2 are the first two identified common activators of all p53 family members. All these results suggest that ASPP1 and ASPP2 could suppress tumor growth even in tumors expressing mutant p53.

scholarly journals MicroRNA-34a Attenuates Paclitaxel Resistance in Prostate Cancer Cells via Direct Suppression of JAG1/Notch1 Axis

2018 ◽  
Vol 50 (1) ◽  
pp. 261-276 ◽  
Author(s):  
Xiaobing Liu ◽  
Xing Luo ◽  
Yuqi Wu ◽  
Ding Xia ◽  
Wei Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Western Blot ◽  
Target Genes ◽  
Luciferase Reporter Assay ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Qrt Pcr

Background/Aims: Treatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically centered on paclitaxel-based chemotherapy. In this study, we aimed to evaluate whether miR-34a attenuates chemoresistance to paclitaxel by regulating target genes associated with drug resistance. Methods: We used data from The Cancer Genome Atlas to compare miR-34a expression levels in prostate cancer (PC) tissues with normal prostate tissues. The effects of miR-34a inhibition and overexpression on PC proliferation were evaluated in vitro via Cell Counting Kit-8 (CCK-8) proliferation, colony formation, apoptosis, and cell-cycle assays. A luciferase reporter assay was employed to identify the interactions between miR-34a and specific target genes. To determine the effects of up-regulation of miR-34a on tumor growth and chemo-resistance in vivo, we injected PC cells overexpressing miR-34a into nude mice subcutaneously and evaluated the rate of tumor growth during paclitaxel treatment. We examined changes in the expression levels of miR-34a target genes JAG1 and Notch1 and their downstream genes via miR-34a transfection by quantitative reverse transcription PCR (qRT-PCR) and western blot assay. Results: miR-34a served as an independent predictor of reduced patient survival. MiR-34a was down-regulated in PC-3PR cells compared with PC-3 cells. The CCK-8 assay showed that miR-34a overexpression resulted in increased sensitivity to paclitaxel while miR-34a down-regulation resulted in chemoresistance to paclitaxel in vitro. A study of gain and loss in a series of functional assays revealed that PC cells expressing miR-34a were chemosensitive. Furthermore, the overexpression of miR-34a increased the sensitivity of PC-3PR cells to chemotherapy in vivo. The luciferase reporter assay confirmed that JAG1 and Notch1 were directly targeted by miR-34a. Interestingly, western blot analysis and qRT-PCR confirmed that miR-34a inhibited the Notch1 signaling pathway. We found that miR-34a increased the chemosensitivity of PC-3PR cells by directly repressing the TCF1/ LEF1 axis. Conclusion: Our results showed that miR-34a is involved in the development of chemosensitivity to paclitaxel. By regulating the JAG1/Notch1 axis, miR-34a or its target genes JAG1 or Notch1 might serve as potential predictive biomarkers of response to paclitaxel-based chemotherapy and/or therapeutic targets that will help to overcome chemoresistance at the mCRPC stage.

scholarly journals Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro

2020 ◽  
Vol 117 (18) ◽  
pp. 9973-9980 ◽  
Author(s):  
Asiya Gusa ◽  
Jonathan D. Williams ◽  
Jang-Eun Cho ◽  
Anna Floyd Averette ◽  
Sheng Sun ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Target Genes ◽  
Opportunistic Infections ◽  
Temperature Shift ◽  
Antifungal Drugs ◽  
Rnai Pathway ◽  
Human Pathogens ◽  
Human Fungal Pathogen

When transitioning from the environment, pathogenic microorganisms must adapt rapidly to survive in hostile host conditions. This is especially true for environmental fungi that cause opportunistic infections in immunocompromised patients since these microbes are not well adapted human pathogens. Cryptococcus species are yeastlike fungi that cause lethal infections, especially in HIV-infected patients. Using Cryptococcus deneoformans in a murine model of infection, we examined contributors to drug resistance and demonstrated that transposon mutagenesis drives the development of 5-fluoroorotic acid (5FOA) resistance. Inactivation of target genes URA3 or URA5 primarily reflected the insertion of two transposable elements (TEs): the T1 DNA transposon and the TCN12 retrotransposon. Consistent with in vivo results, increased rates of mutagenesis and resistance to 5FOA and the antifungal drugs rapamycin/FK506 (rap/FK506) and 5-fluorocytosine (5FC) were found when Cryptococcus was incubated at 37° compared to 30° in vitro, a condition that mimics the temperature shift that occurs during the environment-to-host transition. Inactivation of the RNA interference (RNAi) pathway, which suppresses TE movement in many organisms, was not sufficient to elevate TE movement at 30° to the level observed at 37°. We propose that temperature-dependent TE mobilization in Cryptococcus is an important mechanism that enhances microbial adaptation and promotes pathogenesis and drug resistance in the human host.

scholarly journals Targeting CD47/TNFAIP8 by miR-155 overcomes drug resistance and inhibits tumor growth through induction of phagocytosis and apoptosis in multiple myeloma

Haematologica ◽  
2019 ◽  
Vol 105 (12) ◽  
pp. 2813-2823 ◽  
Author(s):  
Nasrin Rastgoo ◽  
Jian Wu ◽  
Mariah Liu ◽  
Maryam Pourabdollah ◽  
Eshetu G. Atenafu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Tumor Growth ◽  
Myeloma Cell ◽  
Therapeutic Modality ◽  
Drug Resistant ◽  
Myeloma Cells ◽  
Advanced Stages

The mechanisms of drug resistance in multiple myeloma are poorly understood. Here we show that CD47, an integrin-associated receptor, is significantly upregulated in drug resistant myeloma cells in comparison with parental cells, and that high expression of CD47 detected by immunohistochemistry is associated with shorter progression free and overall survivals in multiple myeloma patients. We show that miR-155 is expressed at low levels in drug resistant myeloma cells and is a direct regulator of CD47 through its 3'UTR. Furthermore, low miR-155 levels are associated with advanced stages of disease. MiR-155 overexpression suppressed CD47 expression on myeloma cell surface, leading to induction of phagocytosis of myeloma cells by macrophages and inhibition of tumor growth. MiR-155 overexpression also re-sensitized drug-resistant myeloma cells to bortezomib leading to cell death through targeting TNFAIP8, a negative mediator of apoptosis in vitro and in vivo. Thus, miR-155 mimics may serve as a promising new therapeutic modality by promoting phagocytosis and inducing apoptosis in patients with refractory/relapsed multiple myeloma.

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