The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42

Zhu, Zhongqi; Yu, Zhuang; Rong, Zeyin; Luo, Zai; Zhang, Jing; Qiu, Zhengjun; Huang, Chen

doi:10.7150/thno.36256

Cited by 66 publications

(73 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data were showed as mean ± SD. *P < 0.05, **P < 0.01 GC-related circRNAs have been well recognized [48]. In the present study, it is the first research shows that circCCDC9/miR-6792-3p/CAV1 pathway participates in GC progression.…”

Section: Discussionmentioning

confidence: 51%

Circular RNA circCCDC9 acts as a miR-6792-3p sponge to suppress the progression of gastric cancer through regulating CAV1 expression

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: As a novel type of noncoding RNAs, covalently closed circular RNAs (circRNAs) are ubiquitously expressed in eukaryotes. Emerging studies have related dysregulation of circRNAs to tumorigenesis. However, the biogenesis, regulation, function and mechanism of circRNAs in gastric cancer (GC) remain largely unclear. Methods: The expression profile of circRNAs in 6 pairs of GC tissues and adjacent non-tumor tissues was analyzed by RNA-sequencing. Quantitative real-time PCR was used to determine the expression level of circCCDC9 in GC tissues and cell lines. Then, functional experiments in vitro and in vivo were employed to explore the effects of circCCDC9 on tumor growth and metastasis in GC. Mechanistically, dual luciferase reporter, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to confirm that circCCDC9 directly sponged miR-6792-3p and alleviated suppression on target CAV1 expression. Results: Evidently down-regulated expression of circCCDC9 was observed in both GC tissues and cell lines. Expression of circCCDC9 was negatively correlated with tumor size, lymph node invasion, advanced clinical stage and overall survival in GC patients. Functionally, overexpression of circCCDC9 significantly inhibited the proliferation, migration and invasion of GC cell lines in vitro and tumor growth and metastasis in vivo, whereas miR-6792-3p mimics counteracted these effects. Mechanistic analysis demonstrated that circCCDC9 acted as a "ceRNA" of miR-6792-3p to relieve the repressive effect of miR-6792-3p on its target CAV1, then suppressed the tumorigenesis of GC. Conclusions: CircCCDC9 functions as a tumor suppressor in inhibiting the progression of GC through miR-6792-3p/ CAV1 axis, which has provided an exploitable biomarker and therapeutic target for patients with GC.

show abstract

Section: Discussionmentioning

confidence: 51%

Circular RNA circCCDC9 acts as a miR-6792-3p sponge to suppress the progression of gastric cancer through regulating CAV1 expression

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, the antiapoptotic protein Bcl‐2 was decreased in HCT8 and RKO cells when expression of GINS4 was downregulated (Figure 5B,D). Our previous study indicated that GINS4 inhibited cell apoptosis in vitro and promoted cell growth and metastasis in vitro and in vivo in gastric cancer; GINS4 directly combined and activated Rac1/CDC42, thereby activating their downstream pathways, including the PI3K/AKT, MAPK/ERK, and PTEN pathways in gastric cancer 23 . We examined the activity of the 3 signaling pathway cascades, and found that GINS4 knockdown only decreased the expression of pERK and pAKT in CRC cell lines (Figure 5D).…”

Section: Resultsmentioning

confidence: 99%

“…A novel study reported that the PI3K/AKT signaling pathway increased C‐myc and facilitated cell growth in CRC 36 . Here, our results showed that GINS4 knockdown simultaneously trigged apoptosis and cell cycle arrest and suppressed the MAPK/ERK and PI3K/AKT signaling pathways, which are 2 main downstream pathways of GINS4 identified in our previous study 23 …”

Section: Discussionmentioning

confidence: 99%

“…Luciferase reporter assay confirmed that KLF4 can bind to particular GINS4 promoter elements and transcriptionally inhibit GINS4 expression. Downregulation of miR‐370 could suppress GINS4 expression in bladder cancers, 16 and our recent study showed that circMLLT10 served as a miR‐509‐3‐5p sponge and promoted gastric cancer cell growth and metastasis by increasing GINS4 expression and activating Rac1 and CDC42 23 . Therefore, the relationships between noncoding RNA and KLF4 in regulating GINS4 require further study, which might contribute to exploring the progression of CRC.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

GINS complex subunit 4, a prognostic biomarker and reversely mediated by Krüppel‐like factor 4, promotes the growth of colorectal cancer

et al. 2020

Self Cite

View full text Add to dashboard Cite

| 1203 wileyonlinelibrary.com/journal/cas | INTRODUC TI ONColorectal cancer is the third most common tumor and the third leading cause of cancer-related death in man and women in the world. 1,2 In China, there was an increase of over 376 300 cases of CRC and a total of 191 000 deaths during 2015. 3 Environmental and lifestyle changes, including an altered diet, lack of appropriate physical activity, circadian disruption, and increase in alcohol consumption, have enormously aggravated the burden of CRC. 4 In the past several years, the incidence and mortality of CRC increased rapidly and the onset age was muchThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractGINS complex subunit 4 (GINS4) is essential for DNA replication initiation and elongation in the G 1 /S phase cell cycle in eukaryotes, however, its functional roles and molecular mechanisms remain unclear in many aspects. Our study was designed to investigate the clinical significance, biological function, and molecular mechanism of GINS4 in colorectal cancer (CRC). First, we confirmed that GINS4 expression was significantly overexpressed in CRC cells and tissues. The immunohistochemical results in tissue microarray from 106 CRC patients showed that a high level of GINS4 expression was positively correlated with advanced T stage, higher tumor TNM stage, and poor differentiation. The results from univariate and multivariate survival analysis models based on 106 CRC patients revealed that GINS4 might serve as an independent prognostic indicator for overall survival and disease-free survival of CRC patients.Moreover, downregulated GINS4 can inhibit growth and the cell cycle and accelerate cell apoptosis progression in vitro as well as inhibit tumorigenesis in vivo. Besides, our results also indicated that Krüppel-like factor 4 (KLF4) can negatively regulate GINS4 expression at the transcriptional level and the KLF/GINS4 pathway might play a vital role in the growth and prognosis of CRC. K E Y W O R D Sbiomarker, colorectal cancer, GINS4, growth, KLF4

show abstract

“…Increasing evidence has implied that circRNAs have many microRNA response elements (MREs), which can affect the expression and biological functions of miRNAs via competing (ceRNAs) or molecular sponges [26]. We therefore searched Starbase and found that cARF1 was the appropriate circRNA that harbors one conjectural binding site of miR-342-3p ( Fig.…”

Section: The Carf1 Acts As a Sponge Of Mir-342-3pmentioning

confidence: 99%

The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells

Jiang

Zhou

Zhao

et al. 2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Glioma is the most common and lethal primary brain tumor in adults, and angiogenesis is one of the key factors contributing to its proliferation, aggressiveness, and malignant transformation. However, the discovery of novel oncogenes and the study of its molecular regulating mechanism based on circular RNAs (circRNAs) may provide a promising treatment target in glioma. Methods Bioinformatics analysis, qPCR, western blotting, and immunohistochemistry were used to detect the expression levels of ISL2, miR-342–3p, circRNA ARF1 (cARF1), U2AF2, and VEGFA. Patient-derived glioma stem cells (GSCs) were established for the molecular experiments. Lentiviral-based infection was used to regulate the expression of these molecules in GSCs. The MTS, EDU, Transwell, and tube formation assays were used to detect the proliferation, invasion, and angiogenesis of human brain microvessel endothelial cells (hBMECs). RNA-binding protein immunoprecipitation, RNA pull-down, dual-luciferase reporter, and chromatin immunoprecipitation assays were used to detect the direct regulation mechanisms among these molecules. Results We first identified a novel transcription factor related to neural development. ISL2 was overexpressed in glioma and correlated with poor patient survival. ISL2 transcriptionally regulated VEGFA expression in GSCs and promoted the proliferation, invasion, and angiogenesis of hBMECs via VEGFA-mediated ERK signaling. Regarding its mechanism of action, cARF1 upregulated ISL2 expression in GSCs via miR-342–3p sponging. Furthermore, U2AF2 bound to and promoted the stability and expression of cARF1, while ISL2 induced the expression of U2AF2, which formed a feedback loop in GSCs. We also showed that both U2AF2 and cARF1 had an oncogenic effect, were overexpressed in glioma, and correlated with poor patient survival. Conclusions Our study identified a novel feedback loop among U2AF2, cARF1, miR-342–3p, and ISL2 in GSCs. This feedback loop promoted glioma angiogenesis, and could provide an effective biomarker for glioma diagnosis and prognostic evaluation, as well as possibly being used for targeted therapy.

show abstract

The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42

Cited by 66 publications

References 48 publications

Circular RNA circCCDC9 acts as a miR-6792-3p sponge to suppress the progression of gastric cancer through regulating CAV1 expression

Circular RNA circCCDC9 acts as a miR-6792-3p sponge to suppress the progression of gastric cancer through regulating CAV1 expression

GINS complex subunit 4, a prognostic biomarker and reversely mediated by Krüppel‐like factor 4, promotes the growth of colorectal cancer

The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells

Contact Info

Product

Resources

About