scholarly journals Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Renjie Dou ◽  
Jinjun Qian ◽  
Wei Wu ◽  
Yanxin Zhang ◽  
Yuxia Yuan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Type I ◽  
Disease Course ◽  
Mtor Signaling Pathway ◽  
Hairpin Rna ◽  
Aberrant Expression ◽  
Transcriptomic Sequencing ◽  
Family Protein ◽  
Cellular Apoptosis ◽  
Autophagic Process

AbstractSteroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy–apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.

Electron microscopy analysis of degenerating pancreatic ß cells in transgenic mice expressing the MHC Class I antigen Dd

1990 ◽  
Vol 48 (3) ◽  
pp. 548-549
Author(s):  
T. A. Stewart ◽  
D. Liggitt ◽  
S. Pitts ◽  
L. Martin ◽  
M. Siegel ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Disease Process ◽  
Class Ii ◽  
Class I ◽  
Type I ◽  
Aberrant Expression ◽  
Mhc Molecules ◽  
Endogenous Insulin ◽  
Class Ii Mhc ◽  
Ifn Γ

Insulin-dependant (Type I) diabetes mellitus (IDDM) is a metabolic disorder resulting from the lack of endogenous insulin secretion. The disease is thought to result from the autoimmune mediated destruction of the insulin producing ß cells within the islets of Langerhans. The disease process is probably triggered by environmental agents, e.g. virus or chemical toxins on a background of genetic susceptibility associated with particular alleles within the major histocompatiblity complex (MHC). The relation between IDDM and the MHC locus has been reinforced by the demonstration of both class I and class II MHC proteins on the surface of ß cells from newly diagnosed patients as well as mounting evidence that IDDM has an autoimmune pathogenesis. In 1984, a series of observations were used to advance a hypothesis, in which it was suggested that aberrant expression of class II MHC molecules, perhaps induced by gamma-interferon (IFN γ) could present self antigens and initiate an autoimmune disease. We have tested some aspects of this model and demonstrated that expression of IFN γ by pancreatic ß cells can initiate an inflammatory destruction of both the islets and pancreas and does lead to IDDM.

scholarly journals Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 396
Author(s):  
Timon A. Bloedjes ◽  
Guus de Wilde ◽  
Jeroen E. J. Guikema
Keyword(s):  
Multiple Myeloma ◽  
Cell Metabolism ◽  
Chromosomal Rearrangements ◽  
Chromosomal Translocations ◽  
Metabolic Effects ◽  
Aberrant Expression ◽  
Metabolic Functions ◽  
Complex Chromosomal Rearrangements ◽  
Cancer Cell Metabolism ◽  
The Many

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

scholarly journals Clinical analysis of 40 multiple myeloma patients with extramedullary plasmacytoma of the head

2016 ◽  
Vol 44 (6) ◽  
pp. 1462-1473 ◽  
Author(s):  
Wan-jun Sun ◽  
Jia-jia Zhang ◽  
Na An ◽  
Men Shen ◽  
Zhong-xia Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Characteristics ◽  
Median Overall Survival ◽  
Progression Free Survival ◽  
Clinical Analysis ◽  
Extramedullary Plasmacytoma ◽  
Disease Course ◽  
Combined Chemotherapy ◽  
Free Survival ◽  
Aggressive Disease

Objectives To investigate the clinical characteristics, survival and prognosis of patients with multiple myeloma (MM) and head extramedullary plasmacytoma (EMP). Methods Forty MM patients were enrolled in the study (18 men, 22 women; median age, 55 years). Results Median overall survival (OS) and progression-free survival (PFS) were 24 (5–78) months and 17 (2–36) months, respectively. The 2-, 3- and 5-year OS rates were 51%, 20% and 7%, respectively. The 2-year PFS was 15%. Median OS and PFS in patients administered velcade were 26 (18–50) and 22.5 (5–78) months, compared with 20 (10–30) and 13.5 (2–36) months in patients without velcade, respectively. Median OS was 23.5 (5–50) months in patients with EMP at MM diagnosis ( n = 25) and 36 (22–78) months in patients with head EMP diagnosed during the disease course ( n = 15). Sixteen MM patients had EMP invasion of the head only and 24 had invasion at multiple sites. Median OS was 25 (22–78) months in patients with EMP of the head only and 22 (5–78) months in patients with EMP invasion at multiple sites. Conclusion MM patients with head EMP show a more aggressive disease course and shorter OS and PFS. The prognosis of these patients is poor, especially in patients with head EMP at MM diagnosis, though combined chemotherapy and radiotherapy may prolong survival.

T-cell epitopes within the complementarity-determining and framework regions of the tumor-derived immunoglobulin heavy chain in multiple myeloma

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4930-4936 ◽  
Author(s):  
Lotta Hansson ◽  
Hodjattallah Rabbani ◽  
Jan Fagerberg ◽  
Anders Österborg ◽  
Håkan Mellstedt
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Heavy Chain ◽  
T Cell Response ◽  
Class I ◽  
Type I ◽  
T Cell Epitopes ◽  
Hla Binding

Abstract The idiotypic structure of the monoclonal immunoglobulin (Ig) in multiple myeloma (MM) might be regarded as a tumor-specific antigen. The present study was designed to identify T-cell epitopes of the variable region of the Ig heavy chain (VH) in MM (n = 5) using bioinformatics and analyze the presence of naturally occurring T cells against idiotype-derived peptides. A large number of human-leukocyte-antigen (HLA)–binding (class I and II) peptides were identified. The frequency of predicted epitopes depended on the database used: 245 in bioinformatics and molecular analysis section (BIMAS) and 601 in SYFPEITHI. Most of the peptides displayed a binding half-life or score in the low or intermediate affinity range. The majority of the predicted peptides were complementarity-determining region (CDR)–rather than framework region (FR)–derived (52%-60% vs 40%-48%, respectively). Most of the predicted peptides were confined to the CDR2-FR3-CDR3 “geographic” region of the Ig-VH region (70%), and significantly fewer peptides were found within the flanking (FR1-CDR1-FR2 and FR4) regions (P < .01). There were 8– to 10–amino acid (aa) long peptides corresponding to the CDRs and fitting to the actual HLA-A/B haplotypes that spontaneously recognized, albeit with a low magnitude, type I T cells (interferon γ), indicating an ongoing major histocompatibility complex (MHC) class I–restricted T-cell response. Most of those peptides had a low binding half-life (BIMAS) and a low/intermediate score (SYFPEITHI). Furthermore, 15- to 20-aa long CDR1-3–derived peptides also spontaneously recognized type I T cells, indicating the presence of MHC class II–restricted T cells as well. This study demonstrates that a large number of HLA-binding idiotypic peptides can be identified in patients with MM. Such peptides may spontaneously induce a type I MHC class I– as well as class II–restricted memory T-cell response.

RUNX2 promotes malignant progression in gastric cancer by regulating COL1A1

2021 ◽  
pp. 1-12
Author(s):  
Yanlei Li ◽  
Ran Sun ◽  
Xiulan Zhao ◽  
Baocun Sun
Keyword(s):  
Gastric Cancer ◽  
Human Cancer ◽  
Clinical Stage ◽  
Collagen Type I ◽  
Migration And Invasion ◽  
Type I ◽  
Aberrant Expression ◽  
Invasion And Migration ◽  
Protein Levels

BACKGROUND: Runt-related transcription factor 2 (RUNX2) is an important gene that has been implicated in the progression of human cancer. Aberrant expression of RUNX2 predicts gastric cancer (GC) metastasis. However, the molecular mechanism of RUNX2 remains unknown. OBJECTIVE: We hypothesize that RUNX2 promotes GC metastasis by regulating the extracellular matrix component collagen type I alpha 1 (COL1A1). METHODS: The GEPIA database and immunohistochemical staining of 60 GC tissues were used to analyse the correlations between RUNX2 or COL1A1 expression and clinicopathological features, and the Kaplan-Meier method was used to evaluate survival. RT-PCR, western blotting and immunofluorescence were used to detect RUNX2 and COL1A1 expression in GC cells. Migration and invasion assays were performed to assess the influence of RUNX2 and COL1A1 on metastasis. RESULTS: RUNX2 and COL1A1 were highly expressed at both the gene and protein levels in GC, and patients who were positive for RUNX2 and COL1A1 had shorter survival. RUNX2 and COL1A1 expression linearly correlated with each other (r= 0.15, p< 0.01) and with clinical stage and lymph node metastasis (p< 0.05). Overexpressing RUNX2in vitro enhanced COL1A1 expression and promoted GC cell invasion and migration, whereas COL1A1 knockdown inhibited the increase in cell metastatic capacity promoted by RUNX2. In vivo, GC cells overexpressing RUNX2 promoted lung metastasis, and the downregulation of COL1A1 reduced the metastasis promoted by RUNX2. CONCLUSIONS: RUNX2 may promote GC metastasis by regulating COL1A1. RUNX2/COL1A1 can be employed as a novel target for therapy in GC.

Phase Ib trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-β signaling pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8039-8039
Author(s):  
Ehsan Malek ◽  
Sunjin Hwang ◽  
Paolo Fabrizio Caimi ◽  
Leland L. Metheny ◽  
Benjamin Kent Tomlinson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Immune System ◽  
Transforming Growth Factor ◽  
Single Agent ◽  
Cell Activity ◽  
Type I ◽  
Phase Ib ◽  
Progression Of Disease ◽  
Grade Iii

8039 Background: Immunosuppression and osteoclast activation are two hallmarks of the bone marrow environment in Multiple Myeloma (MM). Corticosteroids have been used historically as part of anti-myeloma regimens due to their anti-plasma cell activity, however they potentially could suppress immune system and activate osteoclast further; therefore there is an unmet need for corticosteroid-free approaches in the era of emerging anti-cancer immunotherapy modalities. There is an abundance of Transforming Growth Factor-beta (TGF-β), a crucial cytokine in suppression of immune system as well as catabolic bone remodeling, in the MM microenvironment. Vactosertib (Vacto) is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model. Here, we report the phase Ib trial of Vacto in combination with pomalidomide (Pom) without any corticosteroids (NCT03143985). Methods: pts with relapsed MM with at least two lines of therapies enrolled on a 3 + 3 dose escalation design and received Vacto, 60 mg/d, 120 mg/d, 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The primary objectives of the study was to assess safety and recommended phase 2 dose. Vacto tablets, taken once or twice daily for 5 days followed by 2 days without treatment, is administered in 28-day cycles, until progression of disease or intolerable toxicity. Results: 15 pts were enrolled on the study (Table). The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt, one episode of grade III renal failure that took less than 7 days to get back to baseline on another patient, sinus bradycardia that reversed to sinus rythem and an Afib that was rate controlled with beta blocerks. No grade IV non-hematologic AE was observed. Three pts had grade III hematologic AE, no grade IV hematologic AE. Three out of 15 pts experienced progression of disease (PFS-6: 80%). Conclusions: The phase Ib data shows safety of this agent in combination with Pom. The efficacy assessment (PFS-6: 80%) is higher than the historical control (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Clinical trial information: NCT03143985. [Table: see text]

scholarly journals Aβ-Induced Repressor Element 1-Silencing Transcription Factor (REST) Gene Delivery Suppresses Activation of Microglia-Like BV-2 Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Tongya Yu ◽  
Hui Quan ◽  
Yuzhen Xu ◽  
Yunxiao Dou ◽  
Feihong Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Activation ◽  
Type I ◽  
Hairpin Rna ◽  
Cell Dysfunction ◽  
Repressor Element

Compelling evidence from basic molecular biology has demonstrated the crucial role of microglia in the pathogenesis of Alzheimer’s disease (AD). Microglia were believed to play a dual role in both promoting and inhibiting Alzheimer’s disease progression. It is of great significance to regulate the function of microglia and make them develop in a favorable way. In the present study, we investigated the function of repressor element 1-silencing transcription factor (REST) in Aβ1-42-induced BV-2 cell dysfunction. We concluded that Aβ1-42 could promote type I activation of BV-2 cells and induce cell proliferation, migration, and proinflammation cytokine TNF-α, IL-1β, and IL-6 expression. Meanwhile, REST was upregulated, and nuclear translocalization took place due to Aβ1-42 stimulation. When REST was knocked down by a specific short hairpin RNA (sh-RNA), BV-2 cell proliferation, migration, and proinflammation cytokine expression and secretion induced by Aβ1-42 were increased, demonstrating that REST may act as a repressor of microglia-like BV-2 cell activation.

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