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Open accessJournal ArticleDOI: 10.1016/J.OMTN.2020.08.037

circRNA circARNT2 Suppressed the Sensitivity of Hepatocellular Carcinoma Cells to Cisplatin by Targeting the miR-155-5p/PDK1 Axis

05 Mar 2021-Molecular therapy. Nucleic acids (Cell Press)-Vol. 23, pp 244-254
Abstract: Circular RNA (circRNA) is a novel subclass of noncoding-RNA molecules that participate in development and progression of a variety of human diseases via sponging microRNAs (miRNAs). Until now, the contributions of circRNAs in chemoresistance of hepatocellular carcinoma (HCC) remain largely unknown. In the present study, we aimed to investigate the role of circRNA in cisplatin resistance of HCC. We investigated the expression of circRNAs in 5 paired cisplatin-sensitive and cisplatin-resistant HCC tissues by microarray analysis. The qRT-PCR analysis was to investigate the expression pattern of circARNT2 in HCC patient tissues and cell lines. Then, the effects of circARNT2 on cisplatin resistance, cell proliferation, and apoptosis were assessed in HCC in vitro and in vivo. circARNT2 was significantly upregulated in HCC tissues and cell lines. Overexpression of circARNT2 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival in patients with HCC. In vitro experiments showed that knockdown of circARNT2 inhibited cell proliferation and enhances the cisplatin sensitivity of HCC cells. Furthermore, circARNT2 facilitates HCC progression in vivo. We demonstrated that circARNT2 acts as a sponge for miR-155-5p and verified that PDK1 is a novel target of miR-155-5p. In summary, our study demonstrated that circARNT2 modulates cisplatin resistance through miR-155-5p/PDK1 pathway. Our findings indicated that circARNT2 may serve as a promising therapeutic target for overcoming cisplatin resistance for HCC.

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Topics: Cisplatin (51%)
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14 results found


Open accessJournal ArticleDOI: 10.1016/J.BIOPHA.2021.111439
Abstract: Background Curcumin exerts a suppressive effect in tumor growth by acting as a modulator of multiple molecular targets. Circular RNA hsa_circ_0007580 (circ-PRKCA) accelerates the tumorigenesis of non-small cell lung cancer (NSCLC). However, whether curcumin can regulate circ-PRKCA to inhibit NSCLC progression is unclear. Methods Cell viability, colony formation, apoptosis, migration, and invasion were analyzed using Cell Counting Kit-8 (CCK-8), plate clone, flow cytometry, or transwell assay. Expression of circ-PRKCA, microRNA (miR)-384, and ITGB1 mRNA (integrin subunit beta 1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Curcumin repressed NSCLC growth through regulating circ-PRKCA expression was validated by xenograft assay. The targeting relationship between circ-PRKCA or ITGB1 and miR-384 was verified by dual-luciferase reporter assay. The level of ITGB1 protein was measured by western blotting. Results Circ-PRKCA and ITGB1 expression were elevated in NSCLC tissues and cells, but miR-384 had an opposing tendency. After curcumin treatment, the expression tendency of circ-PRKCA, miR-384, and ITGB1 in NSCLC cells was overturned. Furthermore, curcumin impeded viability, colony formation, migration, invasion, and accelerated apoptosis of NSCLC cells, but these impacts were partially reversed by circ-PRKCA elevation, miR-384 downregulation, or ITGB1 overexpression. Also, the inhibitory effect of curcumin on xenograft tumor was further enhanced after circ-PRKCA knockdown. Notably, circ-PRKCA regulated ITGB1 expression through sponging miR-384 in curcumin-treated NSCLC cells. Conclusions Curcumin inhibited NSCLC growth through downregulating circ-PRKCA, which regulated ITGB1 expression by adsorbing miR-384. This study provided a new mechanism to understand how curcumin inhibited the progression of NSCLC.

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Topics: Viability assay (55%), Curcumin (54%), microRNA (52%) ... read more

3 Citations


Journal ArticleDOI: 10.1016/J.CYTO.2021.155649
10 Aug 2021-Cytokine
Abstract: Background Hepatocellular carcinoma (HCC) is a type of malignancy with high mortality. It has been reported Propofol could modulate the tumorigenesis of liver cancer; however, the mechanism by which Propofol regulates the development of HCC is still not clear. Methods CCK8 assay was applied to test the cell viability. Flow cytometry and TUNEL staining were applied to detect the cell apoptosis. Meanwhile, dual luciferase reporter assay was performed to investigate the association between miR-105 and JAK2. In addition, RNA and protein levels were investigated by qRT-PCR and western blot, respectively. Results Propofol significantly suppressed the proliferation of HCC cells via inducing the apoptosis. Consistently, miR-105 upregulation inhibited the proliferation of HCC cells, while downregulation of miR-105 reversed Propofol-induced HCC cell apoptosis. Meanwhile, JAK2 was found to be the direct target of miR-105. Furthermore, Propofol could inactivate JAK2/STAT3 signaling via upregulation of miR-105. Conclusion Propofol significantly attenuated HCC tumorigenesis via mediation of miR-105/JAK2/STAT3 axis. Thereby, Propofol might act as a new agent for the treatment of HCC.

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Topics: Downregulation and upregulation (53%), Viability assay (52%), Apoptosis (51%) ... read more

1 Citations


Open accessJournal ArticleDOI: 10.3389/FPHAR.2021.632201
Kunyuan Wang1, Ganxiang Yu1, Jiaen Lin1, Zhilei Wang1  +5 moreInstitutions (1)
Abstract: Regorafenib resistance is a key limiting factor in the treatment of advanced hepatocellular carcinoma (HCC). Increasing evidence has demonstrated that Berberine (BBR) can synergistically enhance the therapeutic effect of various chemotherapeutic agents. However, the contribution of BBR on regorafenib therapy remains unclear. The purpose of this study was to explore the combined treatment effect of berberine and regorafenib in HCC. We found that BBR enhanced the cytotoxicity of regorafenib in HCC cells. Compared with regorafenib alone, the combined treatment of BBR and regorafenib significantly inhibited the proliferation of HCC cells and induced cellular apoptosis. Meanwhile, the combined treatment group with BBR (10mg/kg/day) and regorafenib (5mg/kg/day) had a dramatic inhibitory effect on the growth of HCC xenograft tumors in nude mice. The increased apoptosis of xenograft tumors was seen in the combined treatment group. Moreover, a comprehensive circular RNA sequencing was performed to identify differentially expressed circRNAs in HCC cells after exposure to 100µM BBR and 5µM regorafenib. The volcano plot and scatter plot analyses revealed that there were 58 up-regulated and 19 down-regulated differentially expressed circRNAs between the combination treatment and control groups. Among them, the expression of hsa_circ_0032029 and hsa_circ_0008928 were up-regulated in HCC cells after treatment with 100µM BBR and 5µM regorafenib. Taken together, this study demonstrated that BBR enhanced the anti-HCC effect of regorafenib both in vitro and in vivo. The synergistic anti-tumor effect of BBR and regorafenib might be related to the up-regulation of hsa_circ_0032029 and hsa_circ_0008928 in HCC cells.

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Topics: Regorafenib (66%)

1 Citations


Open accessJournal ArticleDOI: 10.3389/FONC.2021.699625
Weiwei Zhang1, Ming Zheng1, Shan Kong1, Xian Li1  +5 moreInstitutions (1)
Abstract: Purpose The morbidity and mortality of gastric cancer (GC) remain high worldwide. In recent years, circular RNAs (circRNAs) have attracted widespread attention among cancer researchers due to the stable ring structure. The present work aims to find serum circRNA biomarkers that can be used in clinical applications and effective diagnosis. Methods Hsa_circ_0007507 was extracted through circRNA sequencing. Exonuclease digestion assay, actinomycin D, agarose gel electrophoresis (AGE), and Sanger sequencing verified the potential of hsa_circ_0007507 as a biomarker. Besides, a real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was established to detect the level of expression of hsa_circ_0007507. Twenty cases of GC and the paired adjacent tissues were collected to verify its overexpression. Then, serum samples from 30 cases of colorectal cancer, 30 cases of thyroid cancer, and 30 cases of breast cancer were collected to verify their organ specificity. Additionally, serum samples from 80 healthy people, 62 gastritis patients, 31 intestinal metaplasia patients, and 100 GC patients were collected, and the diagnostic efficacy was evaluated through analysis of the receiver operating characteristic (ROC) curve. Furthermore, 16 post-operative GC samples, samples of 65 relapsed patients and 36 non-relapsed patients were collected to evaluate the prognosis of GC. Results The level of expression of hsa_circ_0007507 in GC tissues was up-regulated (p = 0.0121), which was consistent with the results of circRNA sequencing. Exonuclease digestion assay and actinomycin D confirmed that hsa_circ_0007507 had a stable structure and a longer half-life. In the analysis of organ specificity experiments, serum hsa_circ_0007507 did not have specificity for patients with colorectal cancer (p = 0.5319), thyroid cancer (p = 0.5422), or breast cancer (p = 0.5178). Analysis of diagnostic efficacy indicated that the expression of hsa_circ_0007507 was significantly higher than that of normal people (p <0.0001); the area under the ROC (AUC) was 0.832 (95% CI: 0.771-0.892); the diagnostic power of hsa_circ_0007507 was higher than that of CEA (AUC = 0.765, 95% CI: 0.697-0.833) and CA199 (AUC = 0.587, 95% CI: 0.504-0.67). Through diagnosis using a combination of the three, GC patients could be distinguished from normal people (AUC = 0.849), and higher diagnostic efficiency could be achieved. The expression of serum hsa_circ_0007507 in GC patients significantly decreased after surgery (p = 0.001). Besides, the expression of serum hsa_circ_0007507 in patients with post-operative recurrence was significantly up-regulated again (p = 0.0139). Conclusions Serum hsa_circ_0007507 is differentially expressed in GC patients, post-operative GC patients, gastritis patients, intestinal metaplasia patients and relapsed patients, suggesting that serum hsa_circ_0007507 can be used as a new diagnostic and dynamic monitoring biomarker for GC.

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1 Citations


Open accessPosted ContentDOI: 10.21203/RS.3.RS-402505/V3
17 Aug 2021-
Abstract: Gastric cancer (GC) ranks third in motality among all cancers worldwide. Circular RNAs (circRNAs) play essential roles in the malignant progression and metastasis of gastric cancer. As a transcription factor, FOXP2 is involved in the progression of many tumours. However, the regulation and association between circRNAs and FOXP2 remain to be discovered. In our study, CircST3GAL6 was significantly depressed in GC tissues and cells. circST3GAL6 overexpression inhibited the proliferation, invasion and metastasis of GC cells in vitro and in vivo. Importantly, circST3GAL6 overexpression induced apoptosis and promote autophagy in GC cells. Furthermore, we found that circST3GAL6 sponged miR-300 and subsequently regulated FOXP2. We further revealed that FOXP2 suppressed the activation of the Met/AKT/mTOR axis, a classic pathway that regulates autophagy-mediated proliferation and migration. In summary, our findings revealed that circST3GAL6 functions as a tumour suppressor through the miR-300/FOXP2 axis in GC, regulates apoptosis and autophagy through FOXP2-mediated transcriptional inhibition of the MET axis and may be a biomarker for GC treatment.

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Topics: Autophagy (53%), Blocking (radio) (52%), PI3K/AKT/mTOR pathway (52%) ... read more

1 Citations


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25 results found


Open accessJournal ArticleDOI: 10.3322/CAAC.21492
Abstract: This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions There will be an estimated 181 million new cancer cases (170 million excluding nonmelanoma skin cancer) and 96 million cancer deaths (95 million excluding nonmelanoma skin cancer) in 2018 In both sexes combined, lung cancer is the most commonly diagnosed cancer (116% of the total cases) and the leading cause of cancer death (184% of the total cancer deaths), closely followed by female breast cancer (116%), prostate cancer (71%), and colorectal cancer (61%) for incidence and colorectal cancer (92%), stomach cancer (82%), and liver cancer (82%) for mortality Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality) Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts CA: A Cancer Journal for Clinicians 2018;0:1-31 © 2018 American Cancer Society

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Topics: Cancer registry (78%), Cancer (72%), Breast cancer (63%) ... read more

39,828 Citations


Journal ArticleDOI: 10.1038/NATURE11928
21 Mar 2013-Nature
Abstract: Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.

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Topics: Circular RNA (57%), RNA (52%), RNA splicing (52%) ... read more

4,462 Citations


Journal ArticleDOI: 10.1038/NATURE11993
21 Mar 2013-Nature
Abstract: MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.

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Topics: Circular RNA (63%), Argonaute (54%), RNA (54%) ... read more

4,412 Citations


Open accessJournal ArticleDOI: 10.1038/NBT.2890
William R. Jeck1, Norman E. Sharpless1Institutions (1)
Abstract: Circular RNA transcripts were first identified in the early 1990s but knowledge of these species has remained limited, as their study through traditional methods of RNA analysis has been difficult Now, novel bioinformatic approaches coupled with biochemical enrichment strategies and deep sequencing have allowed comprehensive studies of circular RNA species Recent studies have revealed thousands of endogenous circular RNAs in mammalian cells, some of which are highly abundant and evolutionarily conserved Evidence is emerging that some circRNAs might regulate microRNA (miRNA) function, and roles in transcriptional control have also been suggested Therefore, study of this class of noncoding RNAs has potential implications for therapeutic and research applications We believe the key future challenge for the field will be to understand the regulation and function of these unusual molecules

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Topics: Circular RNA (65%), RNA (56%), microRNA (51%) ... read more

1,498 Citations


Open accessJournal ArticleDOI: 10.1038/NCOMMS11215
Qiupeng Zheng1, Chunyang Bao1, Weijie Guo1, Weijie Guo2  +12 moreInstitutions (2)
Abstract: Circular RNAs (circRNAs) represent a class of widespread and diverse endogenous RNAs that may regulate gene expression in eukaryotes. However, the regulation and function of human circRNAs remain largely unknown. Here we generate ribosomal-depleted RNA sequencing data from six normal tissues and seven cancers, and detect at least 27,000 circRNA candidates. Many of these circRNAs are differently expressed between the normal and cancerous tissues. We further characterize one abundant circRNA derived from Exon2 of the HIPK3 gene, termed circHIPK3. The silencing of circHIPK3 but not HIPK3 mRNA significantly inhibits human cell growth. Via a luciferase screening assay, circHIPK3 is observed to sponge to 9 miRNAs with 18 potential binding sites. Specifically, we show that circHIPK3 directly binds to miR-124 and inhibits miR-124 activity. Our results provide evidence that circular RNA produced from precursor mRNA may have a regulatory role in human cells.

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Topics: Circular RNA (62%), Small nucleolar RNA (57%), Gene silencing (56%) ... read more

1,191 Citations