Extrachromosomal circular MiR-17-92 amplicon promotes HCC

Zou, Sailan; Chen, Shihan; Rao, Guocheng; Zhang, Guixiang; Ma, Ming; Peng, Bo; Du, Xuehui; Huang, Wei; Wang, Lin; Tian, Ye; Fu, Xianghui

doi:10.1097/hep.0000000000000435

Cited by 26 publications

(21 citation statements)

References 52 publications

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“…A direct transcriptional target of MYC is miR-17~92, a polycistronic miRNA locus, transcribed into a single primary transcript that yields 6 mature miRNAs: miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1. The polycistronic miR-17~92 cluster is located at chromosome 13q31.3, a hotspot of common eccDNA breakpoints as found in this study 1 and a region often amplified in lung cancer and B-cell lymphomas. miR-17~92 has 2 paralogues, miR-106b-25 and miR-106a-363 clusters, whose expression results in more diverse and complex outcomes 7 .…”

supporting

confidence: 72%

“…Importantly, the miR-17~92 cluster, in specific cellular contexts, functions as an oncogene and is overexpressed in various cancer types, including breast, lung, colon, prostate, pancreas, thyroid, bladder, gastric, and liver 7 . The oncogenic function of miR-17~92 is mediated by targeting mRNAs encoding tumor-suppressor proteins, including cadherin 1 (CDH1), PTEN, p21, BCL2 like11 (BIM), and glycogen synthase kinase 3 beta (GSK3β), as shown in this study 1 . In addition, earlier studies have shown the induction of miR-17~92 in HBV-infected cells and have linked this induction to downregulation of RNA helicase DEAD-box helicase 5 (DDX5) 8 .…”

mentioning

confidence: 60%

“…In this study 1 the authors used the circle-sequencing (Circle-seq) method, which, in contrast to whole genome sequencing that identifies highly amplified circular DNA, identifies circular DNAs independent of size and copy number. This method uses highly enriched circular DNA, prepared after extended (5-day) treatment with Plasmid-Safe ATP-Dependent DNase for digestion of all linear, genomic DNA, followed by rolling circle amplification.…”

mentioning

confidence: 99%

“…MYC increases transcription of miR-17~92 primary transcript 7 . Zou et al 1 found the miR-17~92-encoding locus (MIR17HG gene) as a passenger on eccDNAs. miR-17~92 miRNAs downregulate various tumor suppressors and their expression correlates to poor-prognosis and younger onset HCC 1 .…”

mentioning

confidence: 99%

“…Zou et al 1 found the miR-17~92-encoding locus (MIR17HG gene) as a passenger on eccDNAs. miR-17~92 miRNAs downregulate various tumor suppressors and their expression correlates to poor-prognosis and younger onset HCC 1 . The dashed red lines identify unanswered mechanistic questions: the biogenesis of miR-17~92-containing eccDNAs, their involvement in the mutagenic process via circular extrachromosomal DNA formation, reinsertion/amplification resulting in tumor heterogeneity, and contribution to poor-prognosis HCC.…”

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confidence: 99%

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Two important players in poor-prognosis hepatocellular carcinoma: Extrachromosomal circular DNA (eccDNA) and its passenger, the oncogenic miR-17~92 locus

Andrisani

2023

Hepatology

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Two important players in poor-prognosis hepatocellular carcinoma: Extrachromosomal circular DNA (eccDNA) and its passenger, the oncogenic miR-17~92 locusThe study by Zou et al [1] provides a comprehensive analysis of extrachromosomal circular DNAs (eccDNA) in human HCC, describing identification of eccDNAs carrying the polycistronic microRNA (miR)-17~92 locus. The authors show that enhanced expression of the encoded miRNAs serves as oncogenic driver in HCC, by downregulating expression of tumor-suppressor proteins. These studies link the polycistronic miR-17~92 locus carried by eccDNA to poor-prognosis and early-onset HCC and opens new research directions toward identifying molecular mechanisms of liver cancer pathogenesis and treatment.With the exception of mitochondrial DNA, extrachromosomal DNA circles are a common feature of cancer cells, found in different sizes and copy numbers. Small eccDNA ranges in size from 100 bps to few megabases (Mb), playing important roles in cancer pathogenesis, evolution of tumor heterogeneity, and drug resistance. [2] EccDNAs are also found in nontumor cells. Interestingly, emerging evidence links eccDNA presence to multiple diseases. [3] How eccDNAs form is not well understood. Models for their mechanism of formation include chromothripsis, DNA damage/double-stand breaks and nonhomologous end-joining, [3] fork stalling and template switching during DNA replication, and R-loop formation during transcription, [4,5] among other mechanisms. EccDNAs likely contribute in forming the larger cancer-specific circular extrachromosomal DNAs (ecDNA) by fusion of noncontiguous chromosomal segments. These cancer-specific ecDNAs are in the megabase-size range, carry oncogenes, and often reinsert into the genome generating the homogeneously staining regions (HSRs) and resulting in gene amplifications. [2,3] EcDNAs have been found to harbor well-known oncogenes including MYC or EGFR, among others. Importantly, MYC is the most amplified gene across all cancers, including HCC. [6] In turn, MYC as a

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supporting

confidence: 72%

mentioning

confidence: 60%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Two important players in poor-prognosis hepatocellular carcinoma: Extrachromosomal circular DNA (eccDNA) and its passenger, the oncogenic miR-17~92 locus

Andrisani

2023

Hepatology

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A Hierarchical Mechanotransduction System: From Macro to Micro

Cao,

Tian,

Tian

et al. 2023

Advanced Science

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Mechanotransduction is a strictly regulated process whereby mechanical stimuli, including mechanical forces and properties, are sensed and translated into biochemical signals. Increasing data demonstrate that mechanotransduction is crucial for regulating macroscopic and microscopic dynamics and functionalities. However, the actions and mechanisms of mechanotransduction across multiple hierarchies, from molecules, subcellular structures, cells, tissues/organs, to the whole‐body level, have not been yet comprehensively documented. Herein, the biological roles and operational mechanisms of mechanotransduction from macro to micro are revisited, with a focus on the orchestrations across diverse hierarchies. The implications, applications, and challenges of mechanotransduction in human diseases are also summarized and discussed. Together, this knowledge from a hierarchical perspective has the potential to refresh insights into mechanotransduction regulation and disease pathogenesis and therapy, and ultimately revolutionize the prevention, diagnosis, and treatment of human diseases.

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