NAR Cancer最新文献

Pan-cancer analysis of promoter activity quantitative trait loci 启动子活性数量性状位点的泛癌分析

NAR Cancer Pub Date : 2023-10-11 DOI: 10.1093/narcan/zcad053

Ran Li, Dongyi Wan, Junnan Liang, Huifang Liang, Haohao Huang, Ganxun Li

{"title":"Pan-cancer analysis of promoter activity quantitative trait loci","authors":"Ran Li, Dongyi Wan, Junnan Liang, Huifang Liang, Haohao Huang, Ganxun Li","doi":"10.1093/narcan/zcad053","DOIUrl":"https://doi.org/10.1093/narcan/zcad053","url":null,"abstract":"Abstract Altered promoter activity has been generally observed in diverse biological processes, including tumorigenesis. Accumulating evidence suggests that employing a quantitative trait locus mapping approach is effective in comprehending the genetic basis of promoter activity. By utilizing genotype data from The Cancer Genome Atlas and calculating corresponding promoter activity values using proActiv, we systematically evaluated the impact of genetic variants on promoter activity and identified &gt;1.0 million promoter activity quantitative trait loci (paQTLs) as both cis- and trans-acting. Additionally, leveraging data from the genome-wide association study (GWAS) catalog, we discovered &gt;1.3 million paQTLs that overlap with known GWAS linkage disequilibrium regions. Remarkably, ∼9324 paQTLs exhibited significant associations with patient prognosis. Moreover, investigating the impact of promoter activity on &gt;1000 imputed antitumor therapy responses among pan-cancer patients revealed &gt;43 000 million significant associations. Furthermore, ∼25 000 significant associations were identified between promoter activity and immune cell abundance. Finally, a user-friendly data portal, Pancan-paQTL (https://www.hbpding.com/PancanPaQTL/), was constructed for users to browse, search and download data of interest. Pancan-paQTL serves as a comprehensive multidimensional database, enabling functional and clinical investigations into genetic variants associated with promoter activity, drug responses and immune infiltration across multiple cancer types.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136254839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Large-scale phenogenomic analysis of human cancers uncovers frequent alterations affecting SMC5/6 complex components in breast cancer. 对人类癌症的大规模表型基因组分析发现了乳腺癌中影响 SMC5/6 复合物成分的频繁改变。

NAR Cancer Pub Date : 2023-09-11 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad047

Shamayita Roy, Arvin Zaker, Arvind Mer, Damien D'Amours

{"title":"Large-scale phenogenomic analysis of human cancers uncovers frequent alterations affecting SMC5/6 complex components in breast cancer.","authors":"Shamayita Roy, Arvin Zaker, Arvind Mer, Damien D'Amours","doi":"10.1093/narcan/zcad047","DOIUrl":"10.1093/narcan/zcad047","url":null,"abstract":"Cancer cells often experience large-scale alterations in genome architecture because of DNA damage and replication stress. Whether mutations in core regulators of chromosome structure can also lead to cancer-promoting loss in genome stability is not fully understood. To address this question, we conducted a systematic analysis of mutations affecting a global regulator of chromosome biology -the SMC5/6 complex- in cancer genomics cohorts. Analysis of 64 959 cancer samples spanning 144 tissue types and 199 different cancer genome studies revealed that the SMC5/6 complex is frequently altered in breast cancer patients. Patient-derived mutations targeting this complex associate with strong phenotypic outcomes such as loss of ploidy control and reduced overall survival. Remarkably, the phenotypic impact of several patient mutations can be observed in a heterozygous context, hence providing an explanation for a prominent role of SMC5/6 mutations in breast cancer pathogenesis. Overall, our findings suggest that genes encoding global effectors of chromosome architecture can act as key contributors to cancer development in humans.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/52/38/zcad047.PMC10495288.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10260072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells. 抑制无义介导的 mRNA 衰变可降低人类纤维肉瘤细胞的致瘤性。

NAR Cancer Pub Date : 2023-09-06 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad048

Sofia Nasif, Martino Colombo, Anne-Christine Uldry, Markus S Schröder, Simone de Brot, Oliver Mühlemann

{"title":"Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells.","authors":"Sofia Nasif, Martino Colombo, Anne-Christine Uldry, Markus S Schröder, Simone de Brot, Oliver Mühlemann","doi":"10.1093/narcan/zcad048","DOIUrl":"10.1093/narcan/zcad048","url":null,"abstract":"Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA decay pathway with roles in cellular stress responses, differentiation, and viral defense. It functions in both quality control and post-transcriptional regulation of gene expression. NMD has also emerged as a modulator of cancer progression, although available evidence supports both a tumor suppressor and a pro-tumorigenic role, depending on the model. To further investigate the role of NMD in cancer, we knocked out the NMD factor SMG7 in the HT1080 human fibrosarcoma cell line, resulting in suppression of NMD function. We then compared the oncogenic properties of the parental cell line, the SMG7-knockout, and a rescue cell line in which we re-introduced both isoforms of SMG7. We also tested the effect of a drug inhibiting the NMD factor SMG1 to distinguish NMD-dependent effects from putative NMD-independent functions of SMG7. Using cell-based assays and a mouse xenograft tumor model, we showed that suppression of NMD function severely compromises the oncogenic phenotype. Molecular pathway analysis revealed that NMD suppression strongly reduces matrix metalloprotease 9 (MMP9) expression and that MMP9 re-expression partially rescues the oncogenic phenotype. Since MMP9 promotes cancer cell migration and invasion, metastasis and angiogenesis, its downregulation may contribute to the reduced tumorigenicity of NMD-suppressed cells. Collectively, our results highlight the potential value of NMD inhibition as a therapeutic approach.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/75/ef/zcad048.PMC10480688.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10177722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CDK2 regulates collapsed replication fork repair in CCNE1-amplified ovarian cancer cells via homologous recombination. CDK2通过同源重组调控ccne1扩增的卵巢癌细胞中坍缩复制叉的修复。

NAR Cancer Pub Date : 2023-09-01 DOI: 10.1093/narcan/zcad039

Victoria E Brown, Sydney L Moore, Maxine Chen, Nealia House, Philip Ramsden, Hsin-Jung Wu, Scott Ribich, Alexandra R Grassian, Yoon Jong Choi

{"title":"CDK2 regulates collapsed replication fork repair in CCNE1-amplified ovarian cancer cells via homologous recombination.","authors":"Victoria E Brown, Sydney L Moore, Maxine Chen, Nealia House, Philip Ramsden, Hsin-Jung Wu, Scott Ribich, Alexandra R Grassian, Yoon Jong Choi","doi":"10.1093/narcan/zcad039","DOIUrl":"https://doi.org/10.1093/narcan/zcad039","url":null,"abstract":"CCNE1 amplification is a common alteration in high-grade serous ovarian cancer and occurs in 15-20% of these tumors. These amplifications are mutually exclusive with homologous recombination deficiency, and, as they have intact homologous recombination, are intrinsically resistant to poly (ADP-ribose) polymerase inhibitors or chemotherapy agents. Understanding the molecular mechanisms that lead to this mutual exclusivity may reveal therapeutic vulnerabilities that could be leveraged in the clinic in this still underserved patient population. Here, we demonstrate that CCNE1-amplified high-grade serous ovarian cancer cells rely on homologous recombination to repair collapsed replication forks. Cyclin-dependent kinase 2, the canonical partner of cyclin E1, uniquely regulates homologous recombination in this genetic context, and as such cyclin-dependent kinase 2 inhibition synergizes with DNA damaging agents in vitro and in vivo. We demonstrate that combining a selective cyclin-dependent kinase 2 inhibitor with a DNA damaging agent could be a powerful tool in the clinic for high-grade serous ovarian cancer.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10373114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9963292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Editorial: DNA repair and nucleic acid therapeutics in cancer. 社论：癌症中的 DNA 修复和核酸疗法。

NAR Cancer Pub Date : 2023-08-28 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad044

Robert W Sobol

引用次数: 0

IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing. IQGAP1 通过 NDUFS4 替代剪接介导细胞核与线粒体之间的交流。

NAR Cancer Pub Date : 2023-08-24 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad046

Vasiliki Papadaki, Zoi Erpapazoglou, Maria Kokkori, Malgorzata Ewa Rogalska, Myrto Potiri, Andrada Birladeanu, Eleni N Tsakiri, Hassan Ashktorab, Duane T Smoot, Katerina Papanikolopoulou, Martina Samiotaki, Panagiota Kafasla

{"title":"IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.","authors":"Vasiliki Papadaki, Zoi Erpapazoglou, Maria Kokkori, Malgorzata Ewa Rogalska, Myrto Potiri, Andrada Birladeanu, Eleni N Tsakiri, Hassan Ashktorab, Duane T Smoot, Katerina Papanikolopoulou, Martina Samiotaki, Panagiota Kafasla","doi":"10.1093/narcan/zcad046","DOIUrl":"10.1093/narcan/zcad046","url":null,"abstract":"Constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer cells, resulting in proliferative advantages, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein regulating AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters an AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate, resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer cells relying highly on mitochondrial respiration.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/92/15/zcad046.PMC10448856.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10100269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer. 内分泌治疗耐药前列腺癌症AR基因拷贝数和结构复杂性的共同进化。

NAR Cancer Pub Date : 2023-08-24 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad045

Andrej Zivanovic, Jeffrey T Miller, Sarah A Munro, Todd P Knutson, Yingming Li, Courtney N Passow, Pijus Simonaitis, Molly Lynch, LeAnn Oseth, Shuang G Zhao, Felix Y Feng, Pernilla Wikström, Eva Corey, Colm Morrissey, Christine Henzler, Benjamin J Raphael, Scott M Dehm

{"title":"Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer.","authors":"Andrej Zivanovic, Jeffrey T Miller, Sarah A Munro, Todd P Knutson, Yingming Li, Courtney N Passow, Pijus Simonaitis, Molly Lynch, LeAnn Oseth, Shuang G Zhao, Felix Y Feng, Pernilla Wikström, Eva Corey, Colm Morrissey, Christine Henzler, Benjamin J Raphael, Scott M Dehm","doi":"10.1093/narcan/zcad045","DOIUrl":"10.1093/narcan/zcad045","url":null,"abstract":"Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. Resolving this is important for developing new therapies and predictive biomarkers. Here, we analyzed 41 CRPC tumors and 6 patient-derived xenografts (PDXs) using linked-read DNA-sequencing, and identified 7 tumors that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. Analysis of PDX models by optical genome mapping and fluorescence in situ hybridization showed that AR residing on extrachromosomal DNA (ecDNA) was an underlying mechanism, and was associated with elevated levels and diversity of AR expression. This study identifies co-evolution of AR gene copy number and structural complexity via ecDNA as a mechanism associated with endocrine therapy resistance.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10448862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10100266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The dynamic process of covalent and non-covalent PARylation in the maintenance of genome integrity: a focus on PARP inhibitors. 共价和非共价 PARylation 在维护基因组完整性中的动态过程：聚焦 PARP 抑制剂。

NAR Cancer Pub Date : 2023-08-21 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad043

Adèle Beneyton, Louis Nonfoux, Jean-Philippe Gagné, Amélie Rodrigue, Charu Kothari, Nurgul Atalay, Michael J Hendzel, Guy G Poirier, Jean-Yves Masson

{"title":"The dynamic process of covalent and non-covalent PARylation in the maintenance of genome integrity: a focus on PARP inhibitors.","authors":"Adèle Beneyton, Louis Nonfoux, Jean-Philippe Gagné, Amélie Rodrigue, Charu Kothari, Nurgul Atalay, Michael J Hendzel, Guy G Poirier, Jean-Yves Masson","doi":"10.1093/narcan/zcad043","DOIUrl":"10.1093/narcan/zcad043","url":null,"abstract":"Poly(ADP-ribosylation) (PARylation) by poly(ADP-ribose) polymerases (PARPs) is a highly regulated process that consists of the covalent addition of polymers of ADP-ribose (PAR) through post-translational modifications of substrate proteins or non-covalent interactions with PAR via PAR binding domains and motifs, thereby reprogramming their functions. This modification is particularly known for its central role in the maintenance of genomic stability. However, how genomic integrity is controlled by an intricate interplay of covalent PARylation and non-covalent PAR binding remains largely unknown. Of importance, PARylation has caught recent attention for providing a mechanistic basis of synthetic lethality involving PARP inhibitors (PARPi), most notably in homologous recombination (HR)-deficient breast and ovarian tumors. The molecular mechanisms responsible for the anti-cancer effect of PARPi are thought to implicate both catalytic inhibition and trapping of PARP enzymes on DNA. However, the relative contribution of each on tumor-specific cytotoxicity is still unclear. It is paramount to understand these PAR-dependent mechanisms, given that resistance to PARPi is a challenge in the clinic. Deciphering the complex interplay between covalent PARylation and non-covalent PAR binding and defining how PARP trapping and non-trapping events contribute to PARPi anti-tumour activity is essential for developing improved therapeutic strategies. With this perspective, we review the current understanding of PARylation biology in the context of the DNA damage response (DDR) and the mechanisms underlying PARPi activity and resistance.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10055753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alkylation of nucleobases by 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) sensitizes PARP1-deficient tumors. 2-氯-N,N-二乙基乙胺盐酸盐（CDEAH）对核碱基的烷基化作用可敏化 PARP1 缺失的肿瘤。

NAR Cancer Pub Date : 2023-08-07 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad042

Minwoo Wie, Keon Woo Khim, Arnold S Groehler Iv, Soomin Heo, Junhyeok Woo, Kook Son, Eun A Lee, Jae Sun Ra, Sung You Hong, Orlando D Schärer, Jang Hyun Choi, Kyungjae Myung

{"title":"Alkylation of nucleobases by 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) sensitizes PARP1-deficient tumors.","authors":"Minwoo Wie, Keon Woo Khim, Arnold S Groehler Iv, Soomin Heo, Junhyeok Woo, Kook Son, Eun A Lee, Jae Sun Ra, Sung You Hong, Orlando D Schärer, Jang Hyun Choi, Kyungjae Myung","doi":"10.1093/narcan/zcad042","DOIUrl":"10.1093/narcan/zcad042","url":null,"abstract":"Targeting BRCA1- and BRCA2-deficient tumors through synthetic lethality using poly(ADP-ribose) polymerase inhibitors (PARPi) has emerged as a successful strategy for cancer therapy. PARPi monotherapy has shown excellent efficacy and safety profiles in clinical practice but is limited by the need for tumor genome mutations in BRCA or other homologous recombination genes as well as the rapid emergence of resistance. In this study, we identified 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) as a small molecule that selectively kills PARP1- and xeroderma pigmentosum A-deficient cells. CDEAH is a monofunctional alkylating agent that preferentially alkylates guanine nucleobases, forming DNA adducts that can be removed from DNA by either a PARP1-dependent base excision repair or nucleotide excision repair. Treatment of PARP1-deficient cells leads to the formation of strand breaks, an accumulation of cells in S phase and activation of the DNA damage response. Furthermore, CDEAH selectively inhibits PARP1-deficient xenograft tumor growth compared to isogenic PARP1-proficient tumors. Collectively, we report the discovery of an alkylating agent inducing DNA damage that requires PARP1 activity for repair and acts synergistically with PARPi.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10338042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Circular stable intronic RNAs possess distinct biological features and are deregulated in bladder cancer. 环状稳定的内含子 RNA 具有独特的生物学特征，在膀胱癌中会发生脱调。

NAR Cancer Pub Date : 2023-08-07 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad041

Asta M Rasmussen, Trine Line H Okholm, Michael Knudsen, Søren Vang, Lars Dyrskjøt, Thomas B Hansen, Jakob S Pedersen

{"title":"Circular stable intronic RNAs possess distinct biological features and are deregulated in bladder cancer.","authors":"Asta M Rasmussen, Trine Line H Okholm, Michael Knudsen, Søren Vang, Lars Dyrskjøt, Thomas B Hansen, Jakob S Pedersen","doi":"10.1093/narcan/zcad041","DOIUrl":"10.1093/narcan/zcad041","url":null,"abstract":"Until recently, intronic lariats were regarded as short-lasting splicing byproducts with no apparent function; however, increasing evidence of stable derivatives suggests regulatory roles. Yet little is known about their characteristics, functions, distribution, and expression in healthy and tumor tissue. Here, we profiled and characterized circular stable intronic sequence RNAs (sisRNAs) using total RNA-Seq data from bladder cancer (BC; n = 457, UROMOL cohort), healthy tissue (n = 46), and fractionated cell lines (n = 5). We found that the recently-discovered full-length intronic circles and the stable lariats formed distinct subclasses, with a surprisingly high intronic circle fraction in BC (∼45%) compared to healthy tissues (0-20%). The stable lariats and their host introns were characterized by small transcript sizes, highly conserved BP regions, enriched BP motifs, and localization in multiple cell fractions. Additionally, circular sisRNAs showed tissue-specific expression patterns. We found nine circular sisRNAs as differentially expressed across early-stage BC patients with different prognoses, and sisHNRNPK expression correlated with progression-free survival. In conclusion, we identify distinguishing biological features of circular sisRNAs and point to specific candidates (incl. sisHNRNPK, sisWDR13 and sisMBNL1) that were highly expressed, had evolutionary conserved sequences, or had clinical correlations, which may facilitate future studies and further insights into their functional roles.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9965732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0