Back-Splicing Transcript Isoforms (Circular RNAs) Affect Biologically Relevant Pathways and Offer an Additional Layer of Information to Stratify NMIBC Patients

Goel, Ankit; Ward, Douglas G.; Gordon, Naheema S.; Abbotts, Ben; Cheng, Kar Keung; James, Nicholas D.; Bryan, Richard T.; Arnold, Roland

doi:10.3389/fonc.2020.00812

Cited by 12 publications

(11 citation statements)

References 42 publications

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“…Regarding PDCD1LG2 (PD-L2) gene expression in UBC, we utilised RNA-seq data from our own analysis of 44 NMIBCs ( 18 ). These data confirmed expression of PDCD1LG2 (PD-L2) in addition to CD274 (PD-L1), although no effect of tumor grade was evident on expression of either gene in this small cohort ( Figures 2A, B ).…”

Section: Resultsmentioning

confidence: 99%

PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium

et al. 2021

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The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder.

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Section: Resultsmentioning

confidence: 99%

PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium

et al. 2021

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“…Gene Ontology (GO) includes biological process classification (BP), cellular component (CC), and molecular function classification (MF). Some studies have pointed out that circRNAs may affect the expression of its parental genes, so the function of circRNAs may be related to the function of its parental gene ( Bolisetty and Graveley, 2013 ; Boeckel et al, 2015 ; Goel et al, 2020 ; Mehta et al, 2020 ). Here, the function of the parental gene is used as a prediction of the function of circRNAs.…”

Section: Resultsmentioning

confidence: 99%

Hsa_Circ_0001860 Promotes Smad7 to Enhance MPA Resistance in Endometrial Cancer via miR-520h

Yuan

Zheng

Sun

et al. 2021

Front. Cell Dev. Biol.

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Background: Medroxyprogesterone acetate (MPA) is one of the most commonly prescribed progestin for the treatment of endometrial cancer (EC). Despite initial benefits, many patients ultimately develop progesterone resistance. Circular RNA (circRNA) is a kind of noncoding RNA, contributing greatly to the development of human tumor. However, the role of circular RNA in MPA resistance is unknown.Methods: We explored the expression profile of circRNAs in Ishikawa cells treated with (ISK/MPA) or without MPA (ISK) by RNA sequencing, and identified a key circRNA, hsa_circ_0001860. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify its expression in MPA-resistant cell lines and tissues. CCK8, Transwell, and flow cytometry were used to evaluate the functional roles of hsa_circ_0001860 in MPA resistance. The interaction between hsa_circ_0001860 and miR-520 h was confirmed by bioinformatics analysis, luciferase reporter assay, and RNA pull-down assay.Results: The expression of hsa_circ_0001860 was significantly downregulated in MPA-resistant cell lines and tissues, and negatively correlated with lymph node metastasis and histological grade of EC. Functional analysis showed that hsa_circ_0001860 knockdown by short hairpin RNA (shRNA) promoted the proliferation, inhibited the apoptosis of Ishikawa cells, and promoted the migration and invasion of Ishikawa cells treated with MPA. Mechanistically, hsa_circ_0001860 promoted Smad7 expression by sponging miR-520 h.Conclusion: Hsa_circ_0001860 plays an important role in the development of MPA resistance in EC through miR-520h/Smad7 axis, and it could be targeted to reverse the MPA resistance in endometrial cancer.

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“… 34 , 35 , 36 Of note, some researchers verified the dysregulation of circRNAs in urine of bladder cancer patients. 37 , 38 , 39 Therefore, with the consideration of the characteristics and accessibility of circRNAs, they are suitable for clinical diagnosis and prognostic prediction in human cancers. Chen and his colleagues 40 found that hsa_circ_0000190 has better sensitivity and specificity for a gastric cancer diagnosis compared to carcinoembryonic antigen (CEA) and CA19-9 (classic biomarkers of gastric cancer).…”

Section: Discussionmentioning

confidence: 99%

Circular RNA circRIMS1 Acts as a Sponge of miR-433-3p to Promote Bladder Cancer Progression by Regulating CCAR1 Expression

Wang

Fan

Cai

et al. 2020

Molecular Therapy - Nucleic Acids

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Circular RNAs (circRNAs), a subclass of noncoding RNAs, are reportedly involved in the progression of various diseases. However, the exact role of circRIMS1, also termed hsa_circ_0132246, in human bladder cancer remains unknown. By performing RNA sequencing comparing bladder cell lines and normal uroepithelial cells, circRIMS1 was selected as a research object. We further verified by qRT-PCR that circRIMS1 is upregulated in both bladder cancer tissue and cell lines. Proliferation, colony-formation, Transwell migration, invasion, apoptosis, western blotting, and in vivo experiments were utilized to clarify the roles of circRIMS1, microRNA (miR)-433-3p, and cell cycle and apoptosis regulator 1 (CCAR1). For mechanistic investigation, RNA pulldown, fluorescence in situ hybridization (FISH), and luciferase reporter assay confirmed the binding of circRIMS1 with miR-433-3p. Inhibition of circRIMS1 suppressed the proliferation, migration, and invasion of bladder cancer cells both in vitro and in vivo . Moreover, the circRIMS1/miR-433-3p/CCAR1 regulatory axis was confirmed to be responsible for the biological functions of circRIMS1. Taken together, our research demonstrated that circRIMS1 promotes tumor growth, migration, and invasion through the miR-433-3p/CCAR1 regulatory axis, representing a potential therapeutic target and biomarker in bladder cancer.

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Back-Splicing Transcript Isoforms (Circular RNAs) Affect Biologically Relevant Pathways and Offer an Additional Layer of Information to Stratify NMIBC Patients

Cited by 12 publications

References 42 publications

PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium

PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium

Hsa_Circ_0001860 Promotes Smad7 to Enhance MPA Resistance in Endometrial Cancer via miR-520h

Circular RNA circRIMS1 Acts as a Sponge of miR-433-3p to Promote Bladder Cancer Progression by Regulating CCAR1 Expression

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