Abstract:CHIP, a co-chaperone protein that interacts with Hsc/Hsp70, has been shown to be under-expressed in pancreatic cancer cells and has demonstrated a potential tumor suppressor property. Nevertheless, the underlying mechanisms of CHIP regulation in pancreatic cancer cells remain unknown. In this study, we found that miR-1178 decreased the translation of the CHIP protein by targeting the 3′-UTR region. We observed that over-expression of miR-1178 facilitated the proliferation, G1/S transition, migration and invasi… Show more
“…Finally, through a biotin-coupled probe pull-down assay and dual luciferase assay, miR-1178-3p was selected and confirmed to be the target miRNA of circ- ZKSCAN1 . MiR-1178-3p, an oncogene reported by Cao Z. et al, targets tumor suppressors in pancreatic cancer [29]. Further experiments have confirmed that miR-1178-3p promotes the progression of BCa and is upregulated in BCa.…”
Background
Circular RNAs (circRNAs) represent a subclass of regulatory RNAs that have been shown to have significant regulatory roles in cancer progression. However, the biological functions of circRNAs in bladder cancer (BCa) are largely unknown.
Methods
Cell invasion models were established, and invasion-related circRNAs were detected by qPCR. Using above method, circ-ZKSCAN1 was picked out for further study. Circ-ZKSCAN1 expression and survival analyses were performed through qPCR. The survival curves were generated by the Kaplan-Meier method, and the log-rank test was used to assess the significance. Cell proliferation, migration and invasion were examined to investigate the function of circ-ZKSCAN1. Tumorigenesis in nude mice was assessed to determine the effect of circ-ZKSCAN1 in bladder cancer. Biotin-coupled probe pull-down assays, FISH and luciferase reporter assays were conducted to confirm the relationship between circ-ZKSCAN1 and microRNA. RNA-seq revealed different molecular changes in downstream genes.
Results
Here, we found that circ-ZKSCAN1 was downregulated in BCa tissues and cell lines. Circ-ZKSCAN1 levels were associated with survival, tumor grade, pathological T stage and tumor recurrence. Overexpressed circ-ZKSCAN1 inhibits cell proliferation, migration, invasion and metastasis in vitro and in vivo. Mechanistically, we demonstrated that circ-ZKSCAN1 upregulated p21 expression by sponging miR-1178-3p, which suppressed the aggressive biological behaviors in bladder cancer.
Conclusions
These results reveal that Circ-ZKSCAN1 acts as a tumor suppressor via a novel circ-ZKSCAN1/miR-1178-3p/p21 axis, which have the important role in the proliferation, migration and invasion ablitities of BCa cells and provide a novel perspective on circRNAs in BCa progression.
“…Finally, through a biotin-coupled probe pull-down assay and dual luciferase assay, miR-1178-3p was selected and confirmed to be the target miRNA of circ- ZKSCAN1 . MiR-1178-3p, an oncogene reported by Cao Z. et al, targets tumor suppressors in pancreatic cancer [29]. Further experiments have confirmed that miR-1178-3p promotes the progression of BCa and is upregulated in BCa.…”
Background
Circular RNAs (circRNAs) represent a subclass of regulatory RNAs that have been shown to have significant regulatory roles in cancer progression. However, the biological functions of circRNAs in bladder cancer (BCa) are largely unknown.
Methods
Cell invasion models were established, and invasion-related circRNAs were detected by qPCR. Using above method, circ-ZKSCAN1 was picked out for further study. Circ-ZKSCAN1 expression and survival analyses were performed through qPCR. The survival curves were generated by the Kaplan-Meier method, and the log-rank test was used to assess the significance. Cell proliferation, migration and invasion were examined to investigate the function of circ-ZKSCAN1. Tumorigenesis in nude mice was assessed to determine the effect of circ-ZKSCAN1 in bladder cancer. Biotin-coupled probe pull-down assays, FISH and luciferase reporter assays were conducted to confirm the relationship between circ-ZKSCAN1 and microRNA. RNA-seq revealed different molecular changes in downstream genes.
Results
Here, we found that circ-ZKSCAN1 was downregulated in BCa tissues and cell lines. Circ-ZKSCAN1 levels were associated with survival, tumor grade, pathological T stage and tumor recurrence. Overexpressed circ-ZKSCAN1 inhibits cell proliferation, migration, invasion and metastasis in vitro and in vivo. Mechanistically, we demonstrated that circ-ZKSCAN1 upregulated p21 expression by sponging miR-1178-3p, which suppressed the aggressive biological behaviors in bladder cancer.
Conclusions
These results reveal that Circ-ZKSCAN1 acts as a tumor suppressor via a novel circ-ZKSCAN1/miR-1178-3p/p21 axis, which have the important role in the proliferation, migration and invasion ablitities of BCa cells and provide a novel perspective on circRNAs in BCa progression.
“…miR-1178 has been reported to act as an oncomiR during pancreatic cancer tumorigenesis [ 20 ]. We found that miR-1178 was also upregulated in human BC tissues and cell lines compared with that in normal bladder tissues and SV-HUC-1 cells (Fig.…”
BackgroundIncreasing evidence has revealed that circular RNAs (circRNAs) play crucial roles in cancer biology. However, the role and underlying regulatory mechanisms of circFNDC3B in bladder cancer (BC) remain unknown.MethodsA cell invasion model was established by repeated transwell assays, and invasion-related circRNAs in BC were identified through an invasion model. The expression of circFNDC3B was detected in 82 BC tissues and cell lines by quantitative real-time PCR. Functional assays were performed to evaluate the effects of circFNDC3B on proliferation, migration and invasion in vitro-, and on tumorigenesis and metastasis in vivo. The relationship between circFNDC3B and miR-1178-3p was confirmed by fluorescence in situ hybridization, pull-down assay and luciferase reporter assay.ResultsIn the present study, we identified a novel circRNA (circFNDC3B) through our established BC cell invasion model. We found that circFNDC3B was dramatically downregulated in BC tissues and correlated with pathological T stage, grade, lymphatic invasion and patients’ overall survival rate. Functionally, overexpression of circFNDC3B significantly inhibited proliferation, migration and invasion both in vitro and in vivo. Mechanistically, circFNDC3B could directly bind to miR-1178-3p, which targeted the 5′UTR of the oncogene G3BP2. Moreover, circFNDC3B acted as a miR-1178-3p sponge to suppress G3BP2, thereby inhibiting the downstream SRC/FAK signaling pathway.ConclusionsCircFNDC3B may serve as a novel tumor suppressive factor and potential target for new therapies in human BC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0908-8) contains supplementary material, which is available to authorized users.
“…7a,b. Interestingly, MIR1178 is a suppressor of CHIP, also known as STUB1 (STIP1 homology and U-box containing protein 1), and loss of CHIP is associated with diabetes 41,42 .Figure 5( a ) Proportions of differential islet ATAC-seq peaks of type 2 diabetic versus non-diabetic donors annotated to different genomic regions. ( b ) Bar graph of differential islet ATAC-seq peaks of type 2 diabetic versus non-diabetic donors that overlap with histone modifications.…”
Section: Resultsmentioning
confidence: 99%
“…These include MIR1178 (Fig. 5c), BACH1 , GABRA2 and STX11 which are known to play a role in beta-cells, islets and diabetes 41,42,49 . Using gene ontology, we further found that the anion transmembrane transporter activity pathway (http://amigo.geneontology.org/amigo/term/GO:0008509) was significantly enriched among the genes annotated to the 88 differential ATAC-seq peaks (P = 8 × 10 −6 , q = 0.02, CTNS , S LC16A14 , ANO6 , ANO5 , GABRA2 and SLC16A7 contributed to the enrichment).…”
Impaired insulin secretion from pancreatic islets is a hallmark of type 2 diabetes (T2D). Altered chromatin structure may contribute to the disease. We therefore studied the impact of T2D on open chromatin in human pancreatic islets. We used assay for transposase-accessible chromatin using sequencing (ATAC-seq) to profile open chromatin in islets from T2D and non-diabetic donors. We identified 57,105 and 53,284 ATAC-seq peaks representing open chromatin regions in islets of non-diabetic and diabetic donors, respectively. The majority of ATAC-seq peaks mapped near transcription start sites. Additionally, peaks were enriched in enhancer regions and in regions where islet-specific transcription factors (TFs), e.g. FOXA2, MAFB, NKX2.2, NKX6.1 and PDX1, bind. Islet ATAC-seq peaks overlap with 13 SNPs associated with T2D (e.g. rs7903146, rs2237897, rs757209, rs11708067 and rs878521 near
TCF7L2
,
KCNQ1
,
HNF1B
,
ADCY5
and
GCK
, respectively) and with additional 67 SNPs in LD with known T2D SNPs (e.g. SNPs annotated to
GIPR
,
KCNJ11
,
GLIS3
,
IGF2BP2
,
FTO
and
PPARG
). There was enrichment of open chromatin regions near highly expressed genes in human islets. Moreover, 1,078 open chromatin peaks, annotated to 898 genes, differed in prevalence between diabetic and non-diabetic islet donors. Some of these peaks are annotated to candidate genes for T2D and islet dysfunction (e.g.
HHEX
,
HMGA2
,
GLIS3
,
MTNR1B
and
PARK2
) and some overlap with SNPs associated with T2D (e.g. rs3821943 near
WFS1
and rs508419 near
ANK1
). Enhancer regions and motifs specific to key TFs including BACH2, FOXO1, FOXA2, NEUROD1, MAFA and PDX1 were enriched in differential islet ATAC-seq peaks of T2D versus non-diabetic donors. Our study provides new understanding into how T2D alters the chromatin landscape, and thereby accessibility for TFs and gene expression, in human pancreatic islets.
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