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YY1 and eIF4A3 are mediators of the cell proliferation, migration and invasion in cholangiocarcinoma promoted by circ-ZNF609 by targeting miR-432-5p to regulate LRRC1.

ABSTRACT: Cholangiocarcinoma is a highly aggressive malignant tumor, and its incidence is increasing all over the world. More and more evidences show that the aberrant expression of circular RNAs play important roles in tumorigenesis and progression. Current studies on the expression and function of circRNAs in cholangiocarcinoma are scarce. In this study, circ-ZNF609 was discovered as a novel circRNA highly expressed in cholangiocarcinoma for the first time. The circ-ZNF609 expression is connected with the advanced TNM stage, lymphatic invasion and survival time in cholangiocarcinoma patients, and can be used as an independent prognostic factor for the patients. Circ-ZNF609 can promote the cholangiocarcinoma cells proliferation, migration and invasion in vitro, it can also catalyze the xenograft growth in vivo. The promoting effect of circ-ZNF609 on cholangiocarcinoma is achieved via oncogene LRRC1 up-regulation through targeting miR-432-5p by endogenous competitive RNA mechanism. In addition, transcription factor YY1 can bind to the promoter of ZNF609 to further facilitate the transcription of circ-ZNF609. RNA binding protein eIF4A3 can bind to the pre-mRNA of circ-ZNF609 which promotes the circ-ZNF609 circular formation. Overall, YY1/eIF4A3/circ-ZNF609/miR-432-5p/LRRC1 have a significant role in progression of cholangiocarcinoma, and circ-ZNF609 is expected to become a novel biomarker for targeted therapy and prognosis evaluation of cholangiocarcinoma.

SUBMITTER: Guan C

PROVIDER: S-EPMC8714144 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Circ-LAMP1 contributes to the growth and metastasis of cholangiocarcinoma via miR-556-5p and miR-567 mediated YY1 activation.

Project description:Dysregulation of circular RNAs (circRNAs) executes important regulatory roles in carcinogenesis. Nonetheless, few studies focused on the mechanisms of circRNAs in cholangiocarcinoma (CCA). qRT-PCR was applied to verify the dysregulated circRNAs in CCA. Fisher's exact test, Kaplan-Meier analysis and Cox regression model were utilized to investigate the clinical implications of circ-LAMP1 in the patients with CCA. The viability, apoptosis, migration and invasion of CCA cells were detected after silencing/overexpression of circ-LAMP1. Xenograft and lung metastasis assays were performed to verify the in vitro results. The regulatory networks of circ-LAMP1 were unveiled by bioinformatic analysis, RNA immunoprecipitation (RIP), RNA pulldown and luciferase reporter assays. Up-regulation of circ-LAMP1 was found in CCA tissue samples and cell lines. Enhanced level of circ-LAMP1 was linked to clinical severity, high post-operative recurrence and poor prognosis for the patients with CCA. Gain/loss-of-function assays confirmed the oncogenic role of circ-LAMP1 in mediating cell growth, apoptosis, migration and invasion. Nevertheless, the level of circ-LAMP1 had no effect on normal biliary epithelium proliferation and apoptosis. Animal study further verified the in vitro data. Mechanistically, circ-LAMP1 directly sponged miR-556-5p and miR-567, thereby releasing their suppression on YY1 at post-transcriptional level. Rescue assay indicated that the oncogenic role of circ-LAMP1 is partially dependent on its modulation of YY1 in CCA. In summary, this study suggested that circ-LAMP1 might be used as a promising biomarker/therapeutic target for CCA.

| S-EPMC8034453 | biostudies-literature

Circ-ZNF609 regulates G1-S progression in rhabdomyosarcoma.

Project description:Circular RNAs (circRNAs) represent a class of covalently closed RNAs, derived from non-canonical splicing events, which are expressed in all eukaryotes and often conserved among different species. We previously showed that the circRNA originating from the ZNF609 locus (circ-ZNF609) acts as a crucial regulator of human primary myoblast growth: indeed, the downregulation of the circRNA, and not of its linear counterpart, strongly reduced the proliferation rate of in vitro cultured myoblasts. To deepen our knowledge about circ-ZNF609 role in cell cycle regulation, we studied its expression and function in rhabdomyosarcoma (RMS), a pediatric skeletal muscle malignancy. We found that circ-ZNF609 is upregulated in biopsies from the two major RMS subtypes, embryonal (ERMS) and alveolar (ARMS). Moreover, we discovered that in an ERMS-derived cell line circ-ZNF609 knock-down induced a specific block at the G1-S transition, a strong decrease of p-Akt protein level and an alteration of the pRb/Rb ratio. Regarding p-Akt, we were able to show that circ-ZNF609 acts by counteracting p-Akt proteasome-dependent degradation, thus working as a new regulator of cell proliferation-related pathways. As opposed to ERMS-derived cells, the circRNA depletion had no cell cycle effects in ARMS-derived cells. Since in these cells the p53 gene resulted downregulated, with a concomitant upregulation of its cell cycle-related target genes, we suggest that this could account for the lack of circ-ZNF609 effect in ARMS.

| S-EPMC6544520 | biostudies-literature

circ-ZNF609 regulates G1-S progression in Rhabdomyosarcoma

Project description:Circular RNAs (circRNAs) represent a class of covalently closed RNAs, derived from a non-canonical splicing event, ubiquitously expressed among Eukaryotes and conserved among different species. We identified a circRNA (circ-ZNF609) involved in the regulation of human primary myoblast proliferation. Upon its depletion, the percentage of proliferating myoblasts was highly reduced. To deepen our knowledge about circ-ZNF609 role in cell cycle regulation, we studied its expression and function in Rhabdomyosarcoma (RMS), a pediatric skeletal muscle malignancy. We found that circ-ZNF609 is up-regulated in biopsies from both the two major RMS subtypes, the alveolar (ARMS) and the embryonal (ERMS), and we discovered that its knock-down blocks proliferation of an ERMS-derived cell line, while it has no effect on ARMS-derived cells. To understand the mechanism through which circ-ZNF609 affects cell proliferation we compared the different effects of circ-ZNF609 depletion in ERMS and ARMS and we identified genes and pathways on which the circRNA acts.

2018-12-14 | GSE117609 | GEO

Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis.

Project description:Circular RNAs (circRNAs) constitute a family of transcripts with unique structures and still largely unknown functions. Their biogenesis, which proceeds via a back-splicing reaction, is fairly well characterized, whereas their role in the modulation of physiologically relevant processes is still unclear. Here we performed expression profiling of circRNAs during in vitro differentiation of murine and human myoblasts, and we identified conserved species regulated in myogenesis and altered in Duchenne muscular dystrophy. A high-content functional genomic screen allowed the study of their functional role in muscle differentiation. One of them, circ-ZNF609, resulted in specifically controlling myoblast proliferation. Circ-ZNF609 contains an open reading frame spanning from the start codon, in common with the linear transcript, and terminating at an in-frame STOP codon, created upon circularization. Circ-ZNF609 is associated with heavy polysomes, and it is translated into a protein in a splicing-dependent and cap-independent manner, providing an example of a protein-coding circRNA in eukaryotes.

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YY1-induced DLEU1/miR-149-5p Promotes Malignant Biological Behavior of Cholangiocarcinoma through Upregulating YAP1/TEAD2/SOX2.

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miR-424-5p represses the metastasis and invasion of intrahepatic cholangiocarcinoma by targeting ARK5.

Project description:MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of many kinds of malignant cancer. MiR-424-5p has been reported to participate in various tumors proliferation and metastasis as a suppressor. On the contrary, miR-424-5p would promote cell proliferation in some tumors. However, the expression of miR-424-5p in intrahepatic cholangiocarcinoma (ICC) is rarely reported and its mechanism remains unclear. Here, we discover that miR-424-5p is frequently downregulated in ICC tissues compared with adjacent normal tissues and in ICC cells. Over-expression of miR-424-5p significantly inhibits the invasion and migration of ICC cells in vitro. Importantly, miR-424-5p is found to be a suppressor of ARK5, by binding to 3'-UTR of ARK5 mRNA and then inhibiting mTOR phosphorylated, thus deregulating epithelial-mesenchymal transition (EMT) of ICC. Furthermore, ARK5 is found to play a role in ICC metastasis and regulating EMT. Knockdown of ARK5 inhibits invasion and migration of ICC, while the over-expression gives an opposite effect. Besides, high-expression of ARK5 is also associated with poor prognosis. In conclusion, our study reveals that miR-424-5p is critical to the invasion, migration and EMT progression in ICC cells. Targeting the pathway described here may be a novel approach to inhibit metastasis of ICC and the restoration of miR-424-5p expression may be a promising strategy for ICC therapy.

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EIF4A3-Induced circ-BNIP3 Aggravated Hypoxia-Induced Injury of H9c2 Cells by Targeting miR-27a-3p/BNIP3.

Project description:Acute myocardial infarction (AMI) results from long-term diminished blood supply diminishment (ischemia) to the heart, and the main reason for ischemia is hypoxia. BCL2 interaction protein 3 (BNIP3) can be upregulated by hypoxia and participates in the mediation of hypoxia-activated apoptosis in cardiac myocyte death. The purpose of this study was to interrogate the mechanism of BNIP3 in hypoxia-activated cardiac myocyte injury. Cell viability and apoptosis were evaluated by Cell counting kit 8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), TdT-mediated dUTP Nick-End Labeling (TUNEL), and caspase-3 activity assays. Molecular interactions were assessed by RNA immunoprecipitation (RIP) and pull-down assays. Gene levels were assessed via quantitative real-time PCR and western blot. BNIP3 expression was upregulated by hypoxia in H9c2 cells. We found that circ-BNIP3 (hsa_circ_0005972), whose annotated gene was BNIP3, was induced by hypoxia and positively regulated BNIP3 expression. Knockdown of BNIP3 or circ-BNIP3 reversed the effect of hypoxia in attenuating H9c2 cell viability and inducing apoptosis. circ-BNIP3 sponged miRNA-27a-3p (miR-27a-3p) to upregulate BNIP3 expression. Moreover, eukaryotic translation initiation factor 4A3 (EIF4A3) bound with the upstream region of the circ-BNIP3 mRNA transcript and induced circ-BNIP3 expression in H9c2 cells. EIF4A3-induced circ-BNIP3 aggravated hypoxia-caused injury of H9c2 cells through targeting miR-27a-3p/BNIP3 pathway, indicating circ-BNIP3 as a new target for relieving hypoxia-induced injury of cardiac myocytes.

| S-EPMC6951839 | biostudies-literature

circ-ZNF609 regulates G1-S progression in Rhabdomyosarcoma

Project description:circ-ZNF609 regulates G1-S progression in Rhabdomyosarcoma

| PRJNA482643 | ENA

LINC01783 facilitates cell proliferation, migration and invasion in non-small cell lung cancer by targeting miR-432-5p to activate the notch pathway.

Project description:BackgroundNon-small cell lung cancer (NSCLC) is a common malignancy around the globe. Increasing long non-coding RNAs (lncRNAs) have been confirmed to be associated with the progression of cancers, including NSCLC. Long intergenic non-protein coding RNA 1783 (LINC01783) is a novel lncRNA and its regulatory function as competing endogenous RNA (ceRNA) has not been studied in NSCLC.MethodsRT-qPCR measured the expression level of LINC01783 in NSCLC cells. CCK-8, EdU, transwell and wound healing assays were conducted to detect cell proliferation, migration and invasion in NSCLC. The relationship between miR-432-5p and LINC01783 along with delta like 1 (DLL-1) was illustrated by RNA pull down, RIP and luciferase reporter assays.ResultsLINC01783 was found remarkably increased in NSCLC cell lines, and down-regulation of LINC01783 suppressed cell proliferation, migration and invasion. Then, we discovered Notch pathway was related to the progression of NSCLC, and DLL-1 expression was reduced by LINC01783 knockdown. Furthermore, DLL-1 overexpression could counteract the suppressive effects of LINC01783 down-regulation on the growth of NSCLC cells. MiR-432-5p was observed to be the mutual miRNA that could bind with both LINC01783 and DLL-1. Overexpression of miR-432-5p inhibited DLL-1 expression. In the rescue assays, miR-432-5p depletion offset the impacts of LINC01783 knockdown, and then DLL-1 silence recovered the influence of miR-432-5p down-regulation on NSCLC cell growth.ConclusionLINC01783 aggravates NSCLC cell growth by regulating Notch pathway and sponging miR-432-5p, being a potential target in the treatment for NSCLC.

| S-EPMC8073972 | biostudies-literature

Circular RNA circ-CCAC1 Facilitates Adrenocortical Carcinoma Cell Proliferation, Migration, and Invasion through Regulating the miR-514a-5p/C22orf46 Axis.

Project description:Adrenocortical carcinoma (ACC) is a rare but clinically aggressive endocrine malignancy. Circular RNAs (circRNAs) were found to play key roles in tumorigenesis. In the current study, we aimed to investigate the functions and mechanisms of a novel circRNA, circ-CCAC1, in ACC cells. circ-CCAC1 expression levels in ACC tissue specimens and cell lines were evaluated by RT-qPCR. Kaplan-Meier analysis was applied to explore the relationship between circ-CCAC1 and patients' prognosis. Cell counting kit-8 (CCK-8), colony formation, acridine orange/ethidium bromide (AO/EB) double fluorescence staining, and Transwell assays were performed to evaluate the functions of circ-CCAC1 in ACC cells. Bioinformatics analysis and a dual-luciferase reporter assay were utilized to explore the mechanisms of circ-CCAC1. As a result, circ-CCAC1 was overexpressed in ACC tissue samples and cell lines and correlated with poor prognosis. Gain- and loss-of-function tests demonstrated that circ-CCAC1 acted as an oncogene in ACC. What is more, circ-CCAC1 enhanced C22orf46 expression by sponging miR-514a-5p in ACC cells. A rescue assay illustrated that circ-CCAC1 facilitated ACC progression through miR-514a-5p/C22orf46 signaling. To sum up, we identified a novel circRNA, circ-CCAC1, which may be used as a potential therapeutic target for ACC.

| S-EPMC7641692 | biostudies-literature

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