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MicroRNAs: Emerging Novel Clinical Biomarkers for Hepatocellular Carcinomas.

Anwar SL, Lehmann U - J Clin Med (2015)

Bottom Line: Unique patterns of microRNA expression have also been implicated as biomarkers for prognosis as well as to predict and monitor therapeutic responses in HCC.However, despite a significant number of studies, a consensus on which microRNA panels, sample types, and methodologies for microRNA expression analysis have to be used has not yet been established.This review focuses on potential values, benefits, and limitations of microRNAs as new clinical markers for diagnosis, prognosis, prediction, and therapeutic monitoring in HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia. sl.anwar@ugm.ac.id.

ABSTRACT
The discovery of small non-coding RNAs known as microRNAs has refined our view of the complexity of gene expression regulation. In hepatocellular carcinoma (HCC), the fifth most frequent cancer and the third leading cause of cancer death worldwide, dysregulation of microRNAs has been implicated in all aspects of hepatocarcinogenesis. In addition, alterations of microRNA expression have also been reported in non-cancerous liver diseases including chronic hepatitis and liver cirrhosis. MicroRNAs have been proposed as clinically useful diagnostic biomarkers to differentiate HCC from different liver pathologies and healthy controls. Unique patterns of microRNA expression have also been implicated as biomarkers for prognosis as well as to predict and monitor therapeutic responses in HCC. Since dysregulation has been detected in various specimens including primary liver cancer tissues, serum, plasma, and urine, microRNAs represent novel non-invasive markers for HCC screening and predicting therapeutic responses. However, despite a significant number of studies, a consensus on which microRNA panels, sample types, and methodologies for microRNA expression analysis have to be used has not yet been established. This review focuses on potential values, benefits, and limitations of microRNAs as new clinical markers for diagnosis, prognosis, prediction, and therapeutic monitoring in HCC.

No MeSH data available.


Related in: MedlinePlus

Biogenesis of microRNA (A) and transcriptional inhibition by microRNA (B). MicroRNA is transcribed from microRNA genes by RNA polymerase II into primordial-microRNAs. Segments of pri-miRNA contain a stem-loop structure that can be recognized by DiGeorge Syndrome Critical Region gene 8 (DGCR8) proteins for subsequent processing by RNase type III Drosha to produce pre-microRNAs. The hairpin-contained pre-microRNAs are then exported from the nucleus to the cytoplasm by a protein complex containing exportin-5 and RNA-GTP. In the cytoplasm, pre-microRNAs are further sliced by RNase type III Dicer, eliciting double-strand, ~22 nucleotide-long, mature microRNAs. After the duplex mature microRNA unwinds, degradation of the other strand follows. The single stranded mature microRNA within the RISC complex can subsequently act as a binding site to the messenger RNA (mRNA) targets. Perfect or nearly perfect complementarity to the 3′ UTR of mRNA results in cleavage of the mRNA targets. Partial complementarity of miRNA results in translational inhibition.
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jcm-04-01631-f001: Biogenesis of microRNA (A) and transcriptional inhibition by microRNA (B). MicroRNA is transcribed from microRNA genes by RNA polymerase II into primordial-microRNAs. Segments of pri-miRNA contain a stem-loop structure that can be recognized by DiGeorge Syndrome Critical Region gene 8 (DGCR8) proteins for subsequent processing by RNase type III Drosha to produce pre-microRNAs. The hairpin-contained pre-microRNAs are then exported from the nucleus to the cytoplasm by a protein complex containing exportin-5 and RNA-GTP. In the cytoplasm, pre-microRNAs are further sliced by RNase type III Dicer, eliciting double-strand, ~22 nucleotide-long, mature microRNAs. After the duplex mature microRNA unwinds, degradation of the other strand follows. The single stranded mature microRNA within the RISC complex can subsequently act as a binding site to the messenger RNA (mRNA) targets. Perfect or nearly perfect complementarity to the 3′ UTR of mRNA results in cleavage of the mRNA targets. Partial complementarity of miRNA results in translational inhibition.

Mentions: MicroRNAs are small non-coding RNAs that function as master regulators of gene expression [5,11]. They are primarily transcribed from microRNA genes by RNA polymerase II into several hundred- to thousand-bp-long primordial-microRNAs that are generally capped with a uniquely-modified base and polyadenylated at the tail [12]. Segments of pri-miRNA contain a stem-loop structure that can be recognized by DiGeorge Syndrome Critical Region gene 8 (DGCR8) proteins for subsequent processing by RNase type III Drosha to produce 65–100 bp long pre-microRNAs. The hairpin contained pre-microRNAs are then exported from the nucleus to the cytoplasm by a protein complex containing exportin-5 and RNA-GTP. In the cytoplasm, pre-microRNAs are further sliced by RNase type III Dicer, eliciting double-strand ~22 nucleotide-long mature microRNAs. These mature microRNAs are then incorporated into RNA-induced silencer complex (RISC). After the duplex mature microRNAs unwinds, degradation of the other strand follows. The single stranded mature microRNA within the RISC complex can subsequently act as a binding site for the messenger RNA (mRNA) targets. Argonaute (Ago) protein family plays a central role in the RISC complex. The PAZ (Piwi/Argonaute/Zwille) domain in Ago proteins is essential for binding to the 3′-end, while the PIWI domain is used to recognize the 5′-end of the guide strand. Perfect or nearly perfect complementarity to the 3′ UTR of mRNA results in cleavage of the mRNA targets. Ago family proteins are generally responsible for cleavage while SKI complex and XRN1 for degradation of target mRNAs [13,14]. However, Ago2 can directly cleave and degrade the mRNAs. On the other hand, partial complementarity of a miRNA to the target mRNA will induce translational inhibition through removal of the cap and adenyl-group from the mRNA target by means of interaction with DCP1-DCP2 and CAF1-CCR4-NOT protein complexes. Removal of the cap and adenyl group affects the mRNA stability [15] microRNAs are implicated to regulate up to 30% of the total human genes thus revealing that microRNAs are the most abundant regulators of gene expression in human [16]. Biogenesis of microRNA is depicted schematically in Figure 1.


MicroRNAs: Emerging Novel Clinical Biomarkers for Hepatocellular Carcinomas.

Anwar SL, Lehmann U - J Clin Med (2015)

Biogenesis of microRNA (A) and transcriptional inhibition by microRNA (B). MicroRNA is transcribed from microRNA genes by RNA polymerase II into primordial-microRNAs. Segments of pri-miRNA contain a stem-loop structure that can be recognized by DiGeorge Syndrome Critical Region gene 8 (DGCR8) proteins for subsequent processing by RNase type III Drosha to produce pre-microRNAs. The hairpin-contained pre-microRNAs are then exported from the nucleus to the cytoplasm by a protein complex containing exportin-5 and RNA-GTP. In the cytoplasm, pre-microRNAs are further sliced by RNase type III Dicer, eliciting double-strand, ~22 nucleotide-long, mature microRNAs. After the duplex mature microRNA unwinds, degradation of the other strand follows. The single stranded mature microRNA within the RISC complex can subsequently act as a binding site to the messenger RNA (mRNA) targets. Perfect or nearly perfect complementarity to the 3′ UTR of mRNA results in cleavage of the mRNA targets. Partial complementarity of miRNA results in translational inhibition.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4555081&req=5

jcm-04-01631-f001: Biogenesis of microRNA (A) and transcriptional inhibition by microRNA (B). MicroRNA is transcribed from microRNA genes by RNA polymerase II into primordial-microRNAs. Segments of pri-miRNA contain a stem-loop structure that can be recognized by DiGeorge Syndrome Critical Region gene 8 (DGCR8) proteins for subsequent processing by RNase type III Drosha to produce pre-microRNAs. The hairpin-contained pre-microRNAs are then exported from the nucleus to the cytoplasm by a protein complex containing exportin-5 and RNA-GTP. In the cytoplasm, pre-microRNAs are further sliced by RNase type III Dicer, eliciting double-strand, ~22 nucleotide-long, mature microRNAs. After the duplex mature microRNA unwinds, degradation of the other strand follows. The single stranded mature microRNA within the RISC complex can subsequently act as a binding site to the messenger RNA (mRNA) targets. Perfect or nearly perfect complementarity to the 3′ UTR of mRNA results in cleavage of the mRNA targets. Partial complementarity of miRNA results in translational inhibition.
Mentions: MicroRNAs are small non-coding RNAs that function as master regulators of gene expression [5,11]. They are primarily transcribed from microRNA genes by RNA polymerase II into several hundred- to thousand-bp-long primordial-microRNAs that are generally capped with a uniquely-modified base and polyadenylated at the tail [12]. Segments of pri-miRNA contain a stem-loop structure that can be recognized by DiGeorge Syndrome Critical Region gene 8 (DGCR8) proteins for subsequent processing by RNase type III Drosha to produce 65–100 bp long pre-microRNAs. The hairpin contained pre-microRNAs are then exported from the nucleus to the cytoplasm by a protein complex containing exportin-5 and RNA-GTP. In the cytoplasm, pre-microRNAs are further sliced by RNase type III Dicer, eliciting double-strand ~22 nucleotide-long mature microRNAs. These mature microRNAs are then incorporated into RNA-induced silencer complex (RISC). After the duplex mature microRNAs unwinds, degradation of the other strand follows. The single stranded mature microRNA within the RISC complex can subsequently act as a binding site for the messenger RNA (mRNA) targets. Argonaute (Ago) protein family plays a central role in the RISC complex. The PAZ (Piwi/Argonaute/Zwille) domain in Ago proteins is essential for binding to the 3′-end, while the PIWI domain is used to recognize the 5′-end of the guide strand. Perfect or nearly perfect complementarity to the 3′ UTR of mRNA results in cleavage of the mRNA targets. Ago family proteins are generally responsible for cleavage while SKI complex and XRN1 for degradation of target mRNAs [13,14]. However, Ago2 can directly cleave and degrade the mRNAs. On the other hand, partial complementarity of a miRNA to the target mRNA will induce translational inhibition through removal of the cap and adenyl-group from the mRNA target by means of interaction with DCP1-DCP2 and CAF1-CCR4-NOT protein complexes. Removal of the cap and adenyl group affects the mRNA stability [15] microRNAs are implicated to regulate up to 30% of the total human genes thus revealing that microRNAs are the most abundant regulators of gene expression in human [16]. Biogenesis of microRNA is depicted schematically in Figure 1.

Bottom Line: Unique patterns of microRNA expression have also been implicated as biomarkers for prognosis as well as to predict and monitor therapeutic responses in HCC.However, despite a significant number of studies, a consensus on which microRNA panels, sample types, and methodologies for microRNA expression analysis have to be used has not yet been established.This review focuses on potential values, benefits, and limitations of microRNAs as new clinical markers for diagnosis, prognosis, prediction, and therapeutic monitoring in HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia. sl.anwar@ugm.ac.id.

ABSTRACT
The discovery of small non-coding RNAs known as microRNAs has refined our view of the complexity of gene expression regulation. In hepatocellular carcinoma (HCC), the fifth most frequent cancer and the third leading cause of cancer death worldwide, dysregulation of microRNAs has been implicated in all aspects of hepatocarcinogenesis. In addition, alterations of microRNA expression have also been reported in non-cancerous liver diseases including chronic hepatitis and liver cirrhosis. MicroRNAs have been proposed as clinically useful diagnostic biomarkers to differentiate HCC from different liver pathologies and healthy controls. Unique patterns of microRNA expression have also been implicated as biomarkers for prognosis as well as to predict and monitor therapeutic responses in HCC. Since dysregulation has been detected in various specimens including primary liver cancer tissues, serum, plasma, and urine, microRNAs represent novel non-invasive markers for HCC screening and predicting therapeutic responses. However, despite a significant number of studies, a consensus on which microRNA panels, sample types, and methodologies for microRNA expression analysis have to be used has not yet been established. This review focuses on potential values, benefits, and limitations of microRNAs as new clinical markers for diagnosis, prognosis, prediction, and therapeutic monitoring in HCC.

No MeSH data available.


Related in: MedlinePlus