EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS/MEK1/ERK1–2 signaling

Wei, Yutian; Lu, Chenfei; Zhou, Peng; Zhao, Lin; Lyu, Xiao; Yin, Jianxing; Shi, Zhumei; You, Yongping

doi:10.1093/neuonc/noaa214

Cited by 132 publications

(88 citation statements)

References 34 publications

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“…8b and c). Previous studies showed that EIF4A3, as a key component of the exon junction complex, promotes the expression of several circRNAs [22][23][24]. Correlation analysis revealed that circRHBDD1 level was positively correlated to the expression level of EIF4A3 (Fig.…”

Section: Eif4a3 Promotes the Expression Of Circrhbdd1mentioning

confidence: 77%

Circrhbdd1 Augments M6a-Dependent Metabolic Reprogramming and Restricts Anti-PD-1 Therapy in Hepatocellular Carcinoma

Cai

Chen

Zhang

et al. 2021

Preprint

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Background Metabolic rewiring of cancer cells reshapes the tumor microenvironment, thereby restricting the response to immunotherapy. Circular RNAs (circRNAs) can influence various cellular processes and have been implicated in hepatocellular carcinoma (HCC). Here, we investigated the role of a novel circRNA circRHBDD1 in HCC metabolic transformation and immunotherapy resistance. Methods CircRNA sequencing was performed to determine the differentially expressed circRNA profile in HCC. RT-qPCR and in situ hybridization were used to verify the dysregulation of circRHBDD1 in two independent HCC cohorts. Univariate and multivariate survival analyses were employed to assess the prognostic significance of circRHBDD1. Loss- and gain-of-function approaches were adopted to evaluate the effects of circRHBDD1 on glycolysis and glutaminolysis. Patient-derived xenograft models were used for in vivo evaluation. RNA pull-down, mass spectrometry, RNA immunoprecipitation, fluorescence in situ hybridization, polysome profiling, and meRIP assays were utilized to explore the molecular mechanisms of circRHBDD1 in HCC. Results We found that circRHBDD1 was significantly upregulated in HCC and associated with unfavorable clinicopathological characteristics and poor survival outcomes. In vitro and in vivo experiments showed that circRHBDD1 facilitated HCC glycolysis and glutaminolysis. Mechanistic studies revealed that circRHBDD1 could recruit YTHDF1 to PIK3R1 mRNA and augment PIK3R1 translation in an m6A-dependent manner, leading to activation of the PI3K/AKT signaling. EIF4A3-mediated exon back-splicing contributed to the upregulation of circRHBDD1. Moreover, targeting of circRHBDD1 was able to improve anti-PD-1 therapy resulting in prolonged survival. Conclusion We identified that the circRHBDD1/YTHDF1/PIK3R1 axis was crucial to metabolic reprogramming of HCC. Suppression of circRHBDD1 could potentially sensitize HCC cells to anti-PD-1 therapy.

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Section: Eif4a3 Promotes the Expression Of Circrhbdd1mentioning

confidence: 77%

Circrhbdd1 Augments M6a-Dependent Metabolic Reprogramming and Restricts Anti-PD-1 Therapy in Hepatocellular Carcinoma

Cai

Chen

Zhang

et al. 2021

Preprint

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“…It has been reported that EIF4A3 is a modulator in RNA splicing [27]. Moreover, EIF4A3 can bind to MMP9 [20], BNIP3 [28]or ASAP1 [29] to induce circMMP9, circ-BNIP3 or circASAP1 expression. Herein, it was found that EIF4A3 induced circ_0084615 expression by binding to ASPH transcript.…”

Section: Discussionmentioning

confidence: 99%

EIF4A3-induced circ_0084615 contributes to the progression of colorectal cancer via miR-599/ONECUT2 pathway

Jiang

Tai

Xie

et al. 2021

J Exp Clin Cancer Res

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Background Colorectal cancer (CRC) is a common malignant tumor. Circular RNAs (circRNAs) have been reported to take part in the progression of CRC. However, the functions of circ_0084615 in CRC development are still undefined. In this study, we aimed to explore the functions and underlying mechanisms of circ_0084615 in CRC. Methods qRT-PCR, western blot assay and IHC assay were utilized for the levels of circ_0084615, miR-599, ONECUT2 or EIF4A3. 5-ethynyl-2’-deoxyuridine (EdU) assay and colony formation assay were conducted for cell proliferation ability. Wound-healing assay and transwell assay were applied to evaluate cell migration and invasion. Tube formation assay was used to analyze angiogenesis ability. RNA immunoprecipitation (RIP) assay, RNA pull down assay and dual-luciferase reporter assay were used to analyze the relationships of circ_0084615, miR-599, ONECUT2 and EIF4A3. Murine xenograft model assay was employed for the role of circ_0084615 in vivo. Results Circ_0084615 was elevated in CRC tissues and was linked to TNM stages, lymph node metastasis, differentiation and overall survival rate. Circ_0084615 knockdown inhibited CRC cell proliferation, migration, invasion and angiogenesis in vitro and hampered tumorigenesis in vivo. Circ_0084615 sponged miR-599 and miR-599 inhibition reversed circ_0084615 knockdown-mediated effects on CRC cell growth, motility and angiogenesis. ONECUT2 was identified as the target gene of miR-599. ONECUT2 overexpression recovered the effects of miR-599 on CRC malignant behaviors. Additionally, EIF4A3 induced circ_0084615 expression. Conclusions EIF4A3-induced circ_0084615 played an oncogenic role in CRC development via miR-599/ONECUT2 axis.

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“…PARP-mediated PARylation of MGMT promotes the repair of temozolomideinduced O6-methylguanine DNA damage and thus promotes cell survival [16]. EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS/MEK1/ERK1-2 signalling [17]. TGF-β1 modulates temozolomide resistance in glioblastoma via altered microRNA processing and elevated MGMT [18].…”

Section: Discussionmentioning

confidence: 99%

Circ-SMO-encoded 193 a.a. Confers Chemotherapy Resistance and Immune Escape to Glioma Stem Cells

Yan

wang

et al. 2021

Preprint

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Background: Emerging evidence indicates that circRNAs and their encoded proteins contribute to the tumorigenesis of glioma; however, the biological function and underlying mechanism of chemotherapy resistance and immune escape are largely known.Methods: We applied qRT-PCR, western blotting and immunohistochemistry to detect the expression level and correlation between Bax and PDL1. We next applied an apoptosis assay to detect chemotherapy resistance and immune escape.Results: Circ-SMO and 193 a.a. were upregulated in temozolomide-resistant tumours and tumour-associated immune escape tumours. Circ-SMO and 193 a.a. inhibited temozolomide-induced cell death and promoted PDL1 expression.Conclusion: Circ-SMO and 193 a.a. promote chemotherapy resistance and immune escape by modulating autophagy and PDL1 expression.

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EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS/MEK1/ERK1–2 signaling

Cited by 132 publications

References 34 publications

Circrhbdd1 Augments M6a-Dependent Metabolic Reprogramming and Restricts Anti-PD-1 Therapy in Hepatocellular Carcinoma

Circrhbdd1 Augments M6a-Dependent Metabolic Reprogramming and Restricts Anti-PD-1 Therapy in Hepatocellular Carcinoma

EIF4A3-induced circ_0084615 contributes to the progression of colorectal cancer via miR-599/ONECUT2 pathway

Circ-SMO-encoded 193 a.a. Confers Chemotherapy Resistance and Immune Escape to Glioma Stem Cells

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