Dataset Information

MiR-451a suppression of IL-6R can inhibit proliferation and increase apoptosis through the JAK2/STAT3 pathway in multiple myeloma.

ABSTRACT: The IL-6R/JAK2/STAT3 pathway mediated by interleukin-6 (IL-6) plays an important role in the occurrence and development of multiple myeloma (MM), which is associated with decreased microRNA-451a. However, the biological function of microRNA-451a in MM remains unclear. The bone marrow (BM) of patients with MM was sampled, and the plasma cells were enriched. BM miR-451a, IL-6 and IL-6R levels and Ki-67 expression intensity were evaluated using reverse transcription-quantitative PCR, ELISA and flow cytometry, respectively. U266 cell proliferation, viability and apoptosis were measured using BrdU, CCK-8 and Annexin V/propidium iodide assays, respectively. Total and phospo-(p-)JAK2 and p-STAT3 levels were measured by western blotting. Dual-luciferase reporter assays were performed to validate the predicted target binding sites. miR-451a expression was low in patients with MM and was associated with the Revised International Staging System (R-ISS) stage. IL-6 concentrations were significantly higher in patients with MM than in normal controls and were inversely associated with miR-451a levels (r=-0.96, P<0.0001). IL-6R levels were positively correlated with the R-ISS stage. miR-451a was downregulated, and IL-6R was upregulated in myeloma cell lines. Treatment with an miR-451a mimic inhibited viability and induced apoptosis in U266 cells. p-JAK2 and p-STAT3 levels were significantly lower in mimic-treated U266 cells than in control cells. Thus, miR-451a was shown to regulate myeloma cell proliferation and apoptosis via the IL-6R/JAK2/STAT3 pathway and may be used to predict patient prognosis.

SUBMITTER: Zhong L

PROVIDER: S-EPMC7583731 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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miR-451a suppression of IL-6R can inhibit proliferation and increase apoptosis through the JAK2/STAT3 pathway in multiple myeloma.

Zhong Ling L Xu Zhuyu Z Jin Xin X He Yuan Y Zhang Jianbo J Jiang Tao T Chen Jiao J

Oncology letters 20201008 6

The IL-6R/JAK2/STAT3 pathway mediated by interleukin-6 (IL-6) plays an important role in the occurrence and development of multiple myeloma (MM), which is associated with decreased microRNA-451a. However, the biological function of microRNA-451a in MM remains unclear. The bone marrow (BM) of patients with MM was sampled, and the plasma cells were enriched. BM miR-451a, IL-6 and IL-6R levels and Ki-67 expression intensity were evaluated using reverse transcription-quantitative PCR, ELISA and flow ...[more]

PMID: 33123250

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Project description:Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM.

Project description:BackgroundMultiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM.MethodsTo delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS).ResultsTo explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered.ConclusionWe conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.

Dataset Information

MiR-451a suppression of IL-6R can inhibit proliferation and increase apoptosis through the JAK2/STAT3 pathway in multiple myeloma.

Publications

miR-451a suppression of IL-6R can inhibit proliferation and increase apoptosis through the JAK2/STAT3 pathway in multiple myeloma.

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