Long non-coding RNA ROR confers arsenic trioxide resistance to HepG2 cells by inhibiting p53 expression

Li, Xinyang; Sun, Donglei; Zhao, Tianhe; Zhang, Zunzhen

doi:10.1016/j.ejphar.2020.172982

Cited by 23 publications

(14 citation statements)

References 33 publications

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“…Furthermore, the elevation of Nrf2 in cytoplasm induced by As 2 O 3 was further significantly enhanced by lncRNA OTUD6B-AS1; however, Nrf2 in the nucleus showed the opposite trend. This discovery was consistent with Li et al's report [ 37 ] and Zhang et al's study [ 38 ]. A marked increase in the generation of ROS exceeds the physiological capacity of SOD and GSH-Px, and the exhaustion of these enzymes reduces their activity, ultimately leading to oxidative damage.…”

Section: Discussionsupporting

confidence: 93%

lncRNA OTUD6B-AS1 Exacerbates As₂O₃-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

Wang

Yang

Han

et al. 2020

Oxidative Medicine and Cellular Longevity

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Arsenic trioxide (As2O3) is a promising effective chemotherapeutic agent for cancer treatment; however, how and through what molecular mechanisms the oxidative damage of As2O3 is controlled remains poorly understood. Recently, the involvement of dysregulated long noncoding RNA ovarian tumor domain containing 6B antisense RNA1 (lncRNA OTUD6B-AS1) in tumorigenesis is established. Here, for the first time, we characterize the regulation of As2O3 in the oxidative damage against bladder cancer via lncRNA OTUD6B-AS1. As2O3 could activate lncRNA OTUD6B-AS1 transcription in bladder cancer cells, and these findings were validated in a xenograft tumor model. Functional assays showed that lncRNA OTUD6B-AS1 dramatically exacerbated As2O3-mediated oxidative damage by inducing oxidative stress. Mechanistically, As2O3 increased levels of metal-regulatory transcription factor 1 (MTF1), which regulates lncRNA OTUD6B-AS1, in response to oxidative stress. Further, lncRNA OTUD6B-AS1 inhibited mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) expression by stabilizing miR-6734-5p, which contributed to cytotoxicity by enhancing oxidative stress. Together, our findings offer new insights into the mechanism of As2O3-induced oxidative damage and identify important factors in the pathway, As2O3/lncRNA OTUD6B-AS1/miR-6734-5p/IDH2, expanding the knowledge of activity of As2O3 as cancer treatment.

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Section: Discussionsupporting

confidence: 93%

lncRNA OTUD6B-AS1 Exacerbates As₂O₃-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

Wang

Yang

Han

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…linc-regulator of reprogramming (ROR) was found to be highly expressed in arsenic trioxide-treated HCC cells. 85 linc-ROR alleviated arsenic trioxide-induced cell apoptosis by lowering p53 expression. miR-24 and miR-221 were verified to downregulate caspase-8 and capsase-3, respectively.…”

Section: Involvement Of Sirnas In Regulating Hcc Chemoresistancementioning

confidence: 95%

The Underlying Mechanisms of Noncoding RNAs in the Chemoresistance of Hepatocellular Carcinoma

Wang

Chen

et al. 2020

Molecular Therapy - Nucleic Acids

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Hepatocellular carcinoma (HCC) is one of the most lethal human malignancies. Chemotherapeutic agents, such as sorafenib and lenvatinib, can improve the outcomes of HCC patients. Nevertheless, chemoresistance has become a major hurdle in the effective treatment of HCC. Noncoding RNAs (ncRNAs), including mircoRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), have been demonstrated to participate in the onset and progression of HCC. Moreover, multiple lines of evidence have indicated that ncRNAs also play a pivotal role in HCC drug resistance. ncRNAs can regulate drug efflux and metabolism, glucose metabolism, cellular death pathways, and malignant characteristics in HCC. A deeper understanding of the molecular mechanisms responsible for ncRNA-mediated drug resistance in HCC will provide new opportunities for improving the treatment of HCC. In this review, we summarize recent findings on the molecular mechanisms by which ncRNAs regulate HCC chemoresistance, as well as their potential clinical implications in overcoming HCC chemoresistance.

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“…We have previously reported that ATO could inhibit the RA synovial angiogenesis via the VEGF functional module; therefore, the results of the present study undoubtedly provided an in-depth insight into the antiangiogenic activities of ATO, revealing a new level of diversity in the regulatory mechanisms of ATO therapy on diseases. So far, there is lack of any report about ATO’s treatment of diseases through circRNA’s relevant mechanisms, since the acknowledgment of the relationship between circRNAs (or other noncoding RNAs such as lncRNA) and ATO, even other chemical drugs, is still limited to toxicology ( Dai et al, 2018 ; Xiao et al, 2018 ) and drug resistance in the field cancer ( Li et al, 2020 ). The different effects of ATO on human health might be associated with the complexity of tissue microenvironment with various inflammatory backgrounds, or even related to the genetic and epigenetic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis is Inhibited by Arsenic Trioxide Through Downregulation of the CircHIPK3/miR-149-5p/FOXO1/VEGF Functional Module in Rheumatoid Arthritis

Zhang

et al. 2021

Front. Pharmacol.

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Angiogenesis is a crucial event in the pathogenesis of rheumatoid arthritis (RA). Arsenic trioxide (ATO, As2O3) has been reported to inhibit synovial angiogenesis via the vascular endothelial growth factor (VEGF)-centered functional module. However, the exact mechanisms of ATO on VEGF modulation remain unclear. Circular RNAs (circRNAs) are emerging as important regulators in RA, and the detailed mechanisms remain largely unknown. Here, we reported a circRNA (circHIPK3), the expression of which was significantly increased in RA fibroblast-like synoviocytes (RA-FLS) after TNF-α induction. Moreover, VEGF content in the supernatants of a RA-FLS and human dermal microvascular endothelial cell (HDMEC) co-culture as well as in RA-FLS co-cultured was significantly elevated in accordance with circHIPK3 levels. This increased VEGF expression may significantly upregulate endothelial tube formation and transwell migration, as well as microvessel sprouting in the ex vivo aortic ring assay. CircHIPK3 was further illustrated to be a sponge for the forkhead box transcription factor O1 (FOXO1)-targeting miR-149-5p, leading to the changing expression of the downstream VEGF. These networked factors mainly form a functional module regulating angiogenesis in RA-FLS, and the expression of this functional module could be significantly downregulated by ATO with a consistently reduced vascularity in vitro. In the collagen-induced arthritis (CIA) mice model, an intra-articular injection of the adeno-associated virus-si-circHIPK3 or ATO was demonstrated to alleviate the synovial VEGF expression and arthritis severity respectively. Thus, we elucidate a previously unknown mechanism between circRNAs and RA, and ATO has a significant protective effect on RA-FLS and CIA synovium via its inhibition of the angiogenic functional module of circHIPK3/miR-149-5p/FOXO1/VEGF, suggesting great potential for the combination therapy of ATO with circHIPK3 silencing.

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Long non-coding RNA ROR confers arsenic trioxide resistance to HepG2 cells by inhibiting p53 expression

Cited by 23 publications

References 33 publications

lncRNA OTUD6B-AS1 Exacerbates As₂O₃-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

lncRNA OTUD6B-AS1 Exacerbates As₂O₃-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

The Underlying Mechanisms of Noncoding RNAs in the Chemoresistance of Hepatocellular Carcinoma

Angiogenesis is Inhibited by Arsenic Trioxide Through Downregulation of the CircHIPK3/miR-149-5p/FOXO1/VEGF Functional Module in Rheumatoid Arthritis

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Long non-coding RNA ROR confers arsenic trioxide resistance to HepG2 cells by inhibiting p53 expression

Cited by 23 publications

References 33 publications

lncRNA OTUD6B-AS1 Exacerbates As2O3-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

lncRNA OTUD6B-AS1 Exacerbates As2O3-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

The Underlying Mechanisms of Noncoding RNAs in the Chemoresistance of Hepatocellular Carcinoma

Angiogenesis is Inhibited by Arsenic Trioxide Through Downregulation of the CircHIPK3/miR-149-5p/FOXO1/VEGF Functional Module in Rheumatoid Arthritis

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lncRNA OTUD6B-AS1 Exacerbates As₂O₃-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

lncRNA OTUD6B-AS1 Exacerbates As₂O₃-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2