MiR-124 induces autophagy-related cell death in cholangiocarcinoma cells through direct targeting of the EZH2–STAT3 signaling axis

Ma, Jun; Weng, Li; Wang, Zhongmin; Jia, Yiping; Liu, Bingyan; Wu, Shaoqiu; Cao, Yan; Sun, Xianjun; Yin, Xiaoxing; Shang, Ming; Mao, Aiwu

doi:10.1016/j.yexcr.2018.02.037

Cited by 37 publications

(41 citation statements)

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“…Among these, miR-124 is of significant interest to our group as an important regulator of autophagy in many diseases. For example, miR-124 exerts a tumor suppressive function by inducing autophagy-related cell death in cholangiocarcinoma cells through directly targeting the enhancer of zeste homolog 2-signal transducer and activator of transcription 3 (STAT3) signaling pathway (50). Hypoxiaresponsive miR-124, a potential therapeutic target for prostate cancer, reduces hypoxia-induced autophagy and enhances radiosensitivity by suppressing protooncogene serine/threonine-protein kinase (PIM1) (51).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

Yao

Zhu

et al. 2019

FASEB j.

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. The evidence for a chronic inflammatory reaction mediated by microglial cells in the brain is particularly strong in PD. In our previous study, we have shown that brain‐specific microRNA‐124 (miR‐124) is significantly down‐regulated in the 1‐methy1‐4‐pheny1‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of PD and that it can also inhibit neuroinflammation during the development of PD. However, further investigation is required to understand whether the abnormal expression of miR‐124 regulates microglial activation. In this study, we found that the expression of sequestosome 1 (p62) and phospho‐p38 mitogen‐activated protein kinases (p‐p38) showed a significant increase in LPS‐treated immortalized murine microglial cell line BV2 cells in an MPTP‐induced mouse model of PD. Knockdown of p62 could suppress the secretion of proinflammatory cytokines and p‐p38 of microglia. Besides, inhibition of p38 suppressed the secretion of proinflammatory cytokines and promoted autophagy in BV2 cells. Moreover, our study is the first to identify a unique role of miR‐124 in mediating the microglial inflammatory response by targeting p62 and p38 in PD. In the microglial culture supernatant transfer model, the knockdown of p62 in BV2 cells prevented apoptosis and death of human neuroblastoma cell lines SH‐SY5Y (SH‐SY5Y) cells following microglia activation. In addition, the exogenous delivery of miR‐124 could suppress p62 and p‐p38 expression and could also attenuate the activation of microglia in the substantia nigra par compacta of MPTP‐treated mice. Taken together, our data suggest that miR‐124 could inhibit neuroinflammation during the development of PD by targeting p62, p38, and autophagy, indicating that miR‐124 could be a potential therapeutic target for regulating the inflammatory response in PD.—Yao, L., Zhu, Z., Wu, J., Zhang, Y., Zhang, H., Sun, X., Qian, C., Wang, B., Xie, L., Zhang, S., Lu, G. MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease. FASEB J. 33,8648–8665 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

Yao

Zhu

et al. 2019

FASEB j.

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“…Finally, the increased expression of miR-124-3p in Olaparib- or AZD2461-treated RMS cells suggests that the modulation of this miRNA is involved in the complex molecular mechanisms underlying the PARPi-mediated cytotoxicity. Interestingly, low expression of miR-124-3p has been observed in different types of human cancers, including RMS (deep sequencing data reported in Megiorni et al 2014), and the restoration of miR-124-3p levels is able to decrease cell survival by promoting apoptosis (Wang et al 2016; Ma et al 2018; Zhang et al 2018). The molecular mechanisms and pathways related to the functions of miR-124-3p in RMS models will be further investigated.…”

Section: Discussionmentioning

confidence: 99%

PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines

Camero

Ceccarelli

Felice

et al. 2018

J Cancer Res Clin Oncol

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PurposePARP inhibitors (PARPi) are used in a wide range of human solid tumours but a limited evidence is reported in rhabdomyosarcoma (RMS), the most frequent childhood soft-tissue sarcoma. The cellular and molecular effects of Olaparib, a specific PARP1/2 inhibitor, and AZD2461, a newly synthesized PARP1/2/3 inhibitor, were assessed in alveolar and embryonal RMS cells both as single-agent and in combination with ionizing radiation (IR).MethodsCell viability was monitored by trypan blue exclusion dye assays. Cell cycle progression and apoptosis were measured by flow cytometry, and alterations of specific molecular markers were investigated by, Real Time PCR, Western blotting and immunofluorescence experiments. Irradiations were carried out at a dose rate of 2 Gy (190 UM/min) or 4 Gy (380 UM/min). Radiosensitivity was assessed by using clonogenic assays.ResultsOlaparib and AZD2461 dose-dependently reduced growth of both RH30 and RD cells by arresting growth at G2/M phase and by modulating the expression, activation and subcellular localization of specific cell cycle regulators. Downregulation of phospho-AKT levels and accumulation of γH2AX, a specific marker of DNA damage, were significantly and persistently induced by Olaparib and AZD2461 exposure, this leading to apoptosis-related cell death. Both PARPi significantly enhanced the effects of IR by accumulating DNA damage, increasing G2 arrest and drastically reducing the clonogenic capacity of RMS-cotreated cells.ConclusionsThis study suggests that the combined exposure to PARPi and IR might display a role in the treatment of RMS tumours compared with single-agent exposure, since stronger cytotoxic effects are induced, and compensatory survival mechanisms are prevented.Electronic supplementary materialThe online version of this article (10.1007/s00432-018-2774-6) contains supplementary material, which is available to authorized users.

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“…Emerging studies have revealed that the miR‐124 could directly target the EZH2 and suppress its expression in various cancers, including cholangiocarcinoma, prostate cancer, gastric cancer and hepatocellular carcinoma . Moreover, miR‐506 was reported to inhibit tumour cell proliferation and metastasis in colon cancer by directly targeting EZH2 .…”

Section: Discussionmentioning

confidence: 99%

Targeting EZH2 as a novel therapeutic strategy for sorafenib‐resistant thyroid carcinoma

Wang

Dai

Yan

et al. 2019

J Cellular Molecular Medi

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Thyroid carcinoma is the most common endocrine malignancy. Surgery, post‐operative selective iodine‐131 and thyroid hormone suppression were the most common methods for the therapy of thyroid carcinoma. Although most patients with differentiated thyroid carcinoma ( DTC ) showed positive response for these therapeutic methods, some patients still have to face the radioactive iodine ( RAI )‐refractory problems. Sorafenib is an oral multikinase inhibitor for patients with advanced RAI refractory DTC . However, the side effects and drug resistance of sorafenib suggest us to develop novel drugs and strategies for the therapy of thyroid carcinoma. In this study, we firstly found that patients with sorafenib resistance showed no significant change in rapidly accelerated fibrosarcoma and VEGFR expression levels compared with sorafenib sensitive patients. Moreover, a further mi RNA s screen by qRT ‐ PCR indicated that miR‐124‐3p and miR‐506‐3p (miR‐124/506) were remarkably reduced in sorafenib insensitive patients. With a bioinformatics prediction and functional assay validation, we revealed that enhancer of zeste homolog 2 ( EZH 2) was the direct target for miR‐124/506. Interestingly, we finally proved that the sorafenib resistant cells regained sensitivity for sorafenib by EZH 2 intervention with miR‐124/506 overexpression or EZH 2 inhibitor treatment in vitro and in vivo, which will lead to the decreased tri‐methylation at lysine 27 of histone H3 (H3K27me3) and increased acetylated lysine 27 of histone H3 (H3K27ac) levels. Therefore, we conclude that the suppression of EZH 2 represents a potential target for thyroid carcinoma therapy.

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MiR-124 induces autophagy-related cell death in cholangiocarcinoma cells through direct targeting of the EZH2–STAT3 signaling axis

Cited by 37 publications

References 50 publications

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines

Targeting EZH2 as a novel therapeutic strategy for sorafenib‐resistant thyroid carcinoma

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