Unique Circular Structure Research Articles

Abstract 3348: Identification of circSPINT2 as a tumor suppressive circular RNA sensitizing lung cancer to 3rd generation EGFR-TKI treatment

Abstract Introduction: Lung cancer remains a high incidence and mortality globally. Adenocarcinoma is the most common type of lung cancer with around 50% of patients in Asia expressing mutated EGFR, which makes EGFR an effective therapeutic target to treat lung adenocarcinoma (LAC). Unfortunately, resistance to EGFR-TKI often occurs in patients through either dynamic EGFR mutation, driver oncogenic pathway shift, or transdifferentiating to evade EGFR-TKI treatment. circRNAs are a type of RNA molecule with a circular shape. Their importance in several biological processes and disease progression was intensively studied recently, and have emerged as promising diagnostic, prognostic, and monitoring biomarkers for diseases like cancer. CircRNAs’ unique circular structure and resistance to degradation make them robust candidates for non-invasive diagnostics of cancers. Aims: This study aimed to identify and investigate the involvement of a novel circular RNA (circSPINT2) in acquired resistance against the 3rd generation EGFR-TKI Osimertinib. Materials & Methods: Comparative circRNA sequencing (circRNA-Seq), qRT-PCR, sanger sequencing, and RNase R treatment were applied to identify and verify the identity of Osimertinib-resistance-related circRNA. Biotinylated circRNA pull-down assay, miRNA-seq, and in-silico analysis were employed to delineate the downstream miRNA-mRNA regulatory axis. Osimertinib-resistant mouse xenograft model was established to explore the molecular mechanisms associated with both circSPINT2 and Osimertinib resistance. Results: We identified circSPINT2 as particularly downregulated in Osimertinib-resistant cell lines (OR) using circRNA-Seq. Overexpression of circSPINT2 in resistant cells increased cellular sensitivity to Osimertinib, whereas knockdown of circSPINT2 conferred Osimertinib resistance in parental cells. The circSPINT2-dependent regulation of Osimertinib sensitivity is mediated through modulating apoptosis. In-vitro analysis indicated high circSPINT2 increased tumor suppressor RBP1 expression by sequestering oncogenic hsa-miR-1296 further improving Osimertinib sensitivity. Molecular and histologic analysis of subcutaneous xenograft tumors corroborated our in-vitro results. Conclusion: Our study demonstrated circSPINT2 functions as a tumor suppressor, improving Osimertinib sensitivity via the hsa-miR-1296/RBP1 axis. circSPINT2 may serve as a prognostic and cancer biomarker to monitor Osimertinib resistance in LAC patients. Citation Format: Mong-Lien (Lotus) Wang, Shih-Hwa Shiou, Yi-Chen Chen, Ming-Long Tsai, Nalini Devi Verusingam, Alan Han-Kiat Ong. Identification of circSPINT2 as a tumor suppressive circular RNA sensitizing lung cancer to 3rd generation EGFR-TKI treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3348.

Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE

Transmembrane E3 ligases play crucial roles in homeostasis. Much protein and organelle quality control, and metabolic regulation, are determined by ER-resident MARCH6 E3 ligases, including Doa10 in yeast. Here, we present Doa10/MARCH6 structural analysis by cryo-EM and AlphaFold predictions, and a structure-based mutagenesis campaign. The majority of Doa10/MARCH6 adopts a unique circular structure within the membrane. This channel is established by a lipid-binding scaffold, and gated by a flexible helical bundle. The ubiquitylation active site is positioned over the channel by connections between the cytosolic E3 ligase RING domain and the membrane-spanning scaffold and gate. Here, by assaying 95 MARCH6 variants for effects on stability of the well-characterized substrate SQLE, which regulates cholesterol levels, we reveal crucial roles of the gated channel and RING domain consistent with AlphaFold-models of substrate-engaged and ubiquitylation complexes. SQLE degradation further depends on connections between the channel and RING domain, and lipid binding sites, revealing how interconnected Doa10/MARCH6 elements could orchestrate metabolic signals, substrate binding, and E3 ligase activity.

Circular RNAs in gynecologic cancers: mechanisms and implications for chemotherapy resistance.

Chemotherapy resistance remains a major challenge in the treatment of gynecologic malignancies. Increasing evidence suggests that circular RNAs (circRNAs) play a significant role in conferring chemoresistance in these cancers. In this review, we summarize the current understanding of the mechanisms by which circRNAs regulate chemotherapy sensitivity and resistance in gynecologic malignancies. We also discuss the potential clinical implications of these findings and highlight areas for future research. CircRNAs are a novel class of RNA molecules that are characterized by their unique circular structure, which confers increased stability and resistance to degradation by exonucleases. Recent studies have shown that circRNAs can act as miRNA sponges, sequestering miRNAs and preventing them from binding to their target mRNAs. This can lead to upregulation of genes involved in drug resistance pathways, ultimately resulting in decreased sensitivity to chemotherapy. We discuss several specific examples of circRNAs that have been implicated in chemoresistance in gynecologic cancers, including cervical cancer, ovarian cancer, and endometrial cancer. We also highlight the potential clinical applications of circRNA-based biomarkers for predicting chemotherapy response and guiding treatment decisions. Overall, this review provides a comprehensive overview of the current state of knowledge regarding the role of circRNAs in chemotherapy resistance in gynecologic malignancies. By elucidating the underlying mechanisms by which circRNAs regulate drug sensitivity, this work has important implications for improving patient outcomes and developing more effective therapeutic strategies for these challenging cancers.

Biological functions and applications of circRNAs-next generation of RNA-based therapy.

Circular RNAs (circRNAs) are unique single-stranded RNA molecules that are covalently closed and expressed in a tissue- and cell-specific manner. Most circRNAs are formed by back-splicing of pre-mRNA and have a wide range of functions in cells. As they lack a 5'-cap and a 3'-poly(A) tail, they are classified as noncoding RNAs that act as sponges for miRNAs and RNA-binding proteins. However, recent studies have found that some circRNAs can undergo cap-independent translation, making them capable of encoding proteins through alternative translation initiation mechanisms. CircRNAs are more stable than linear mRNAs due to their unique circular structure. With mRNA-based drugs receiving significant attention in the past two years, mRNA's instability and immunogenicity are major obstacles to its widespread use. Since circRNA is more stable than mRNA and less immunogenic and can be translated in a tissue-specific manner, it is a promising modality for RNA therapy. In this review, we will provide an overview of the biological functions and potential applications of circRNA.

Silencing mouse circular RNA circSlc8a1 by circular antisense cA-circSlc8a1 induces cardiac hepatopathy

Circular RNAs (circRNAs) are a group of non-coding RNAs with a unique circular structure generated by back-splicing. It is acknowledged that circRNAs play critical roles in cardiovascular diseases. However, functional studies of circRNAs were impeded due to lack of effective invivo silencing approaches. Since most circRNAs are produced by protein-coding transcripts, gene editing typically affects the coding activity of the parental genes. In this study, we developed a circular antisense RNA (cA-circSlc8a1) that could silence the highly expressed circRNA circSlc8a1 in the mouse heart but not its parental Slc8a1 linear mRNA. Transgenic cA-circSlc8a1 mice developed congestive heart failure resulting in a significant increase in the body weight secondary to peripheral edema and congestive hepatopathy. To further test the role of circSlc8a1, we generated transgenic mice overexpressing circSlc8a1 and observed a protective effect of circSlc8a1 in a pressure overload model. Mechanistically, we found that circSlc8a1 translocated into mitochondria to drive ATP synthesis. While establishing a transgenic murine model for antisense-mediated circRNA silencing without interfering with the parental linear RNA, our finding revealed the essential role of circSlc8a1 in maintaining heart function and may lay the groundwork of using the circular antisense RNA as a potential gene therapy approach for cardiovascular diseases.

Circular RNAs: Biogenesis, Function, and a Role as Possible Cancer Biomarkers.

Circular RNAs (circRNAs) are a class of noncoding RNAs (ncRNAs) that form covalently closed continuous loop structures, lacking the terminal 5′ and 3′ ends. CircRNAs are generated in the process of back-splicing and can originate from different genomic regions. Their unique circular structure makes circRNAs more stable than linear RNAs. In addition, they also display insensitivity to ribonuclease activity. Generally, circRNAs function as microRNA (miRNA) sponges and have a regulatory role in transcription and translation. They may be also translated in a cap-independent manner in vivo, to generate specific proteins. In the last decade, next-generation sequencing techniques, especially RNA-seq, have revealed great abundance and also dysregulation of many circRNAs in various diseases, suggesting their involvement in disease development and progression. Regarding their high stability and relatively specific differential expression patterns in tissues and extracellular environment (e.g., body fluids), they are regarded as promising novel biomarkers in cancer. Therefore, we focus this review on describing circRNA biogenesis, function, and involvement in human cancer development and address the potential of circRNAs to be effectively used as novel cancer diagnostic and prognostic biomarkers.

Disease onset and aging in the world of circular RNAs.

Circular ribonucleic acids (circRNAs) are non-coding RNAs of approximately 100 nucleotides in length with thousands of members in mammalian cells. The presence of circRNAs is believed to be even greater than that of messenger RNAs. Identification of circRNAs occurred approximately 37 years ago with the subsequent demonstration that covalent bonds are necessary for the unique circular structure of these ribonucleic acids. However, present understanding of the complex biological role of circRNAs remains limited and requires further elucidation. CircRNAs may impact aging, multiple disorders, function as biomarkers, and are able to regulate gene expression by acting as effective microRNA (miRNA) sponges. New work suggests that circRNAs are vital for the modulation of cellular senescence and programmed cell death pathways such as apoptosis. These non-coding RNAs can control cell cycle progression, cellular proliferation, and cellular survival impacting disorders linked to aging, cardiovascular disease, and atherosclerosis through pathways that involve cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase inhibitor 1 (p21), and mammalian forkhead transcription factors. In addition, circRNAs can oversee cellular metabolism and disorders such as diabetes mellitus through the regulation of insulin signaling as well as limit tumor progression through Wnt signaling and β-catenin pathways. Further understanding of the biology of circRNAs offers great promise for the targeting of novel strategies against a wide spectrum of disease entities.

Upheaval Dome, Utah, USA: Impact origin confirmed

Research Article| March 01, 2008 Upheaval Dome, Utah, USA: Impact origin confirmed Elmar Buchner; Elmar Buchner 1Institut für Planetologie, Universität Stuttgart, 70174 Stuttgart, Germany Search for other works by this author on: GSW Google Scholar Thomas Kenkmann Thomas Kenkmann 2Museum für Naturkunde-Mineralogie, Humboldt-Universität zu Berlin, 10115 Berlin, Germany Search for other works by this author on: GSW Google Scholar Geology (2008) 36 (3): 227–230. https://doi.org/10.1130/G24287A.1 Article history received: 27 Jul 2007 rev-recd: 02 Nov 2007 accepted: 06 Nov 2007 first online: 02 Mar 2017 Cite View This Citation Add to Citation Manager Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Search Site Citation Elmar Buchner, Thomas Kenkmann; Upheaval Dome, Utah, USA: Impact origin confirmed. Geology 2008;; 36 (3): 227–230. doi: https://doi.org/10.1130/G24287A.1 Download citation file: Ris (Zotero) Refmanager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentBy SocietyGeology Search Advanced Search Abstract Upheaval Dome is a unique circular structure on the Colorado Plateau in SE Utah, the origin of which has been controversially discussed for decades. It has been interpreted as a crypto volcanic feature, a salt diapir, a pinched-off salt diapir, and an eroded impact crater. While recent structural mapping, modeling, and analyses of deformation mechanisms strongly support an impact origin, ultimate proof, namely the documentation of unambiguous shock features, has yet to be successfully provided. In this study, we document, for the first time, shocked quartz grains from this crater in sandstones of the Jurassic Kayenta Formation. The investigated grains contain multiple sets of decorated planar deformation features. Transmission electron microscopy (TEM) reveals that the amorphous lamellae are annealed and exhibit dense tangles of dislocations as well as trails of fluid inclusions. The shocked quartz grains were found in the periphery of the central uplift in the northeastern sector of the crater, which most likely represents the cross range crater sector. You do not have access to this content, please speak to your institutional administrator if you feel you should have access.