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Families of microRNAs Expressed in Clusters Regulate Cell Signaling in Cervical Cancer.

Servín-González LS, Granados-López AJ, López JA - Int J Mol Sci (2015)

Bottom Line: Individual miRNA expression is reported without considering that miRNAs are grouped in clusters and may have similar functions, such as the case of clusters with anti-oncomiRs (23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR-99a~125b-2, miR-99b~125a, miR-100~125b-1, miR-199a-2~214, and miR-302s) or oncomiRs activity (miR-1-1~133a-2, miR-1-2~133a-1, miR-133b~206, miR-17~92, miR-106a~363, miR183~96~182, miR-181a-1~181b-1, and miR-181a-2~181b-2), which regulated mitogen-activated protein kinases (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), NOTCH, proteasome-culling rings, and apoptosis cell signaling.In this work we point out the pathways regulated by families of miRNAs grouped in 20 clusters involved in cervical cancer.Reviewing how miRNA families expressed in cluster-regulated cell path signaling will increase the knowledge of cervical cancer progression, providing important information for therapeutic, diagnostic, and prognostic methodology design.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de microRNAs, Unidad Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas, Av. Preparatoria S/N, Zacatecas 98066, Mexico. stevenservin07@gmail.com.

ABSTRACT
Tumor cells have developed advantages to acquire hallmarks of cancer like apoptosis resistance, increased proliferation, migration, and invasion through cell signaling pathway misregulation. The sequential activation of genes in a pathway is regulated by miRNAs. Loss or gain of miRNA expression could activate or repress a particular cell axis. It is well known that aberrant miRNA expression is well recognized as an important step in the development of cancer. Individual miRNA expression is reported without considering that miRNAs are grouped in clusters and may have similar functions, such as the case of clusters with anti-oncomiRs (23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR-99a~125b-2, miR-99b~125a, miR-100~125b-1, miR-199a-2~214, and miR-302s) or oncomiRs activity (miR-1-1~133a-2, miR-1-2~133a-1, miR-133b~206, miR-17~92, miR-106a~363, miR183~96~182, miR-181a-1~181b-1, and miR-181a-2~181b-2), which regulated mitogen-activated protein kinases (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), NOTCH, proteasome-culling rings, and apoptosis cell signaling. In this work we point out the pathways regulated by families of miRNAs grouped in 20 clusters involved in cervical cancer. Reviewing how miRNA families expressed in cluster-regulated cell path signaling will increase the knowledge of cervical cancer progression, providing important information for therapeutic, diagnostic, and prognostic methodology design.

No MeSH data available.


Related in: MedlinePlus

Regulation of JAG1-NOTCH1-uPA, Cyclin D-CDK4/6-p21-p27, and PI3K-PDK1-AKT1 cell signaling by members of the miR-23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR17~92, miR183~96~182, and miR-302s clusters. MiR-34a, a member of the miR-34 family, downregulates JAG1 and NOCTH1 expression. JAG1 is activated by uPA inducing ECM reorganization via plasminogen-plasmin-MMP, inducing the hallmarks of cancer. Protein expression of uPA is decreased by miR-23b, a member of the cluster 23b~27b~24-1. The complex cyclin D-CDK4/6 phosphorylates RB inducing the liberation of E2F, favoring c-Myc, c-Fos and COX-2 transcription provoking cellular division. Cellular division progression is regulated by the inhibition of cyclin D via the miR-302s cluster and CDK4/6 through p18Ink4c, p21, and p27. The PI3K-PDK1-AKT1 axis decreases p21 and p27 protein expression, delivering CDK4/6 to be complexed with cyclin D. This signaling pathway is regulated by the downregulation of AKT due to the miR-302s cluster increasing p21 and p27 proteins, thereby inhibiting the complex cyclin D-CDK4/6. CDK4/6 is inhibited by p18Ink4c, which in turn is downregulated by miR-34a, inducing apoptosis and causing proliferation to diminish. Another point of control is given by the miR-29a~29b-1 cluster hindering CDK4/6, which provokes inhibition of the complex cyclin D-CDK4/6. YY-1, a target of the cluster miR-29a~29b-1, induces transcription of c-Myc in the absence of this cluster common in cervical cancer. Cell cycle continuity is dependent on the levels and the complex formed of cyclin D-CDK4/6 and cyclin E-CDK4/6. FOXO1 could directly hinder CDK4/6, thus impeding the formation and activation of the complex cyclin D-CDK4/6 and cyclin E-CDK4/6 and indirectly via p27. Cyclin D is indirectly upregulated by miR-182, one member of the cluster miR183~96~182, through FOXO1 downregulation conducing to proliferation, migration, invasion, and apoptosis induction. These cellular processes are enhanced via FOXO1 phosphorylation by PI3K-PDK1-AKT, which is recognized by skp2, a subunit of the skip1/cul1/F-box ubiquitin protein complex, targeting it to degradation via proteasomes. MiR-92 diminishes the expression of PTEN, triggering PI3K-PDK1-AKT signaling, which is conducive to FOXO1 reduction. In bold are the miRNAs with effect on genes with validated experimental data.
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ijms-16-12773-f003: Regulation of JAG1-NOTCH1-uPA, Cyclin D-CDK4/6-p21-p27, and PI3K-PDK1-AKT1 cell signaling by members of the miR-23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR17~92, miR183~96~182, and miR-302s clusters. MiR-34a, a member of the miR-34 family, downregulates JAG1 and NOCTH1 expression. JAG1 is activated by uPA inducing ECM reorganization via plasminogen-plasmin-MMP, inducing the hallmarks of cancer. Protein expression of uPA is decreased by miR-23b, a member of the cluster 23b~27b~24-1. The complex cyclin D-CDK4/6 phosphorylates RB inducing the liberation of E2F, favoring c-Myc, c-Fos and COX-2 transcription provoking cellular division. Cellular division progression is regulated by the inhibition of cyclin D via the miR-302s cluster and CDK4/6 through p18Ink4c, p21, and p27. The PI3K-PDK1-AKT1 axis decreases p21 and p27 protein expression, delivering CDK4/6 to be complexed with cyclin D. This signaling pathway is regulated by the downregulation of AKT due to the miR-302s cluster increasing p21 and p27 proteins, thereby inhibiting the complex cyclin D-CDK4/6. CDK4/6 is inhibited by p18Ink4c, which in turn is downregulated by miR-34a, inducing apoptosis and causing proliferation to diminish. Another point of control is given by the miR-29a~29b-1 cluster hindering CDK4/6, which provokes inhibition of the complex cyclin D-CDK4/6. YY-1, a target of the cluster miR-29a~29b-1, induces transcription of c-Myc in the absence of this cluster common in cervical cancer. Cell cycle continuity is dependent on the levels and the complex formed of cyclin D-CDK4/6 and cyclin E-CDK4/6. FOXO1 could directly hinder CDK4/6, thus impeding the formation and activation of the complex cyclin D-CDK4/6 and cyclin E-CDK4/6 and indirectly via p27. Cyclin D is indirectly upregulated by miR-182, one member of the cluster miR183~96~182, through FOXO1 downregulation conducing to proliferation, migration, invasion, and apoptosis induction. These cellular processes are enhanced via FOXO1 phosphorylation by PI3K-PDK1-AKT, which is recognized by skp2, a subunit of the skip1/cul1/F-box ubiquitin protein complex, targeting it to degradation via proteasomes. MiR-92 diminishes the expression of PTEN, triggering PI3K-PDK1-AKT signaling, which is conducive to FOXO1 reduction. In bold are the miRNAs with effect on genes with validated experimental data.

Mentions: The families miR-23, miR-24, and miR-27 are organized in two clusters (Table 1). The cluster miR-23a~27a~24-2 is localized on chromosome 19 while cluster miR-23b~27b~24-1 is on chromosome 9 [4,6,35]. In cervical carcinoma cells it was shown that miR-23b diminished uPA expression via 3′-UTR mRNA binding [36] (Figure 3). This protein is a serine protease that degrades plasminogen to plasmin, thus activating metalloproteinases and inducing extracellular matrix (ECM) degradation. Recently it was shown that an increase of Notch receptors’ expression triggers the Notch pathway by uPA activation [37]. Additionally, JAG-Notch activation stimulates uPA transcription [38,39], inducing a mutual signaling activation exacerbated by miR-23b absence favoring cancer progression (Figure 3). The clusters miR-23a~27a~24-2 and 23b~27b~24-1 have a high similarity; however, it appears that the members of these clusters have opposite profile expressions: whereas miR-27a is upregulated, miR-23b and miR-27b are downregulated in cervical cancer [12]. MiR-23a, miR-27a, and miR-27b from the two clusters have sequences that may potentially regulate uPA (microRNA.org, MIRDB, and Target Scan). It remains to be addressed whether miRNAs of these clusters regulated the same targets to elucidate the participation of these clusters in cervical cancer’s advance.


Families of microRNAs Expressed in Clusters Regulate Cell Signaling in Cervical Cancer.

Servín-González LS, Granados-López AJ, López JA - Int J Mol Sci (2015)

Regulation of JAG1-NOTCH1-uPA, Cyclin D-CDK4/6-p21-p27, and PI3K-PDK1-AKT1 cell signaling by members of the miR-23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR17~92, miR183~96~182, and miR-302s clusters. MiR-34a, a member of the miR-34 family, downregulates JAG1 and NOCTH1 expression. JAG1 is activated by uPA inducing ECM reorganization via plasminogen-plasmin-MMP, inducing the hallmarks of cancer. Protein expression of uPA is decreased by miR-23b, a member of the cluster 23b~27b~24-1. The complex cyclin D-CDK4/6 phosphorylates RB inducing the liberation of E2F, favoring c-Myc, c-Fos and COX-2 transcription provoking cellular division. Cellular division progression is regulated by the inhibition of cyclin D via the miR-302s cluster and CDK4/6 through p18Ink4c, p21, and p27. The PI3K-PDK1-AKT1 axis decreases p21 and p27 protein expression, delivering CDK4/6 to be complexed with cyclin D. This signaling pathway is regulated by the downregulation of AKT due to the miR-302s cluster increasing p21 and p27 proteins, thereby inhibiting the complex cyclin D-CDK4/6. CDK4/6 is inhibited by p18Ink4c, which in turn is downregulated by miR-34a, inducing apoptosis and causing proliferation to diminish. Another point of control is given by the miR-29a~29b-1 cluster hindering CDK4/6, which provokes inhibition of the complex cyclin D-CDK4/6. YY-1, a target of the cluster miR-29a~29b-1, induces transcription of c-Myc in the absence of this cluster common in cervical cancer. Cell cycle continuity is dependent on the levels and the complex formed of cyclin D-CDK4/6 and cyclin E-CDK4/6. FOXO1 could directly hinder CDK4/6, thus impeding the formation and activation of the complex cyclin D-CDK4/6 and cyclin E-CDK4/6 and indirectly via p27. Cyclin D is indirectly upregulated by miR-182, one member of the cluster miR183~96~182, through FOXO1 downregulation conducing to proliferation, migration, invasion, and apoptosis induction. These cellular processes are enhanced via FOXO1 phosphorylation by PI3K-PDK1-AKT, which is recognized by skp2, a subunit of the skip1/cul1/F-box ubiquitin protein complex, targeting it to degradation via proteasomes. MiR-92 diminishes the expression of PTEN, triggering PI3K-PDK1-AKT signaling, which is conducive to FOXO1 reduction. In bold are the miRNAs with effect on genes with validated experimental data.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490472&req=5

ijms-16-12773-f003: Regulation of JAG1-NOTCH1-uPA, Cyclin D-CDK4/6-p21-p27, and PI3K-PDK1-AKT1 cell signaling by members of the miR-23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR17~92, miR183~96~182, and miR-302s clusters. MiR-34a, a member of the miR-34 family, downregulates JAG1 and NOCTH1 expression. JAG1 is activated by uPA inducing ECM reorganization via plasminogen-plasmin-MMP, inducing the hallmarks of cancer. Protein expression of uPA is decreased by miR-23b, a member of the cluster 23b~27b~24-1. The complex cyclin D-CDK4/6 phosphorylates RB inducing the liberation of E2F, favoring c-Myc, c-Fos and COX-2 transcription provoking cellular division. Cellular division progression is regulated by the inhibition of cyclin D via the miR-302s cluster and CDK4/6 through p18Ink4c, p21, and p27. The PI3K-PDK1-AKT1 axis decreases p21 and p27 protein expression, delivering CDK4/6 to be complexed with cyclin D. This signaling pathway is regulated by the downregulation of AKT due to the miR-302s cluster increasing p21 and p27 proteins, thereby inhibiting the complex cyclin D-CDK4/6. CDK4/6 is inhibited by p18Ink4c, which in turn is downregulated by miR-34a, inducing apoptosis and causing proliferation to diminish. Another point of control is given by the miR-29a~29b-1 cluster hindering CDK4/6, which provokes inhibition of the complex cyclin D-CDK4/6. YY-1, a target of the cluster miR-29a~29b-1, induces transcription of c-Myc in the absence of this cluster common in cervical cancer. Cell cycle continuity is dependent on the levels and the complex formed of cyclin D-CDK4/6 and cyclin E-CDK4/6. FOXO1 could directly hinder CDK4/6, thus impeding the formation and activation of the complex cyclin D-CDK4/6 and cyclin E-CDK4/6 and indirectly via p27. Cyclin D is indirectly upregulated by miR-182, one member of the cluster miR183~96~182, through FOXO1 downregulation conducing to proliferation, migration, invasion, and apoptosis induction. These cellular processes are enhanced via FOXO1 phosphorylation by PI3K-PDK1-AKT, which is recognized by skp2, a subunit of the skip1/cul1/F-box ubiquitin protein complex, targeting it to degradation via proteasomes. MiR-92 diminishes the expression of PTEN, triggering PI3K-PDK1-AKT signaling, which is conducive to FOXO1 reduction. In bold are the miRNAs with effect on genes with validated experimental data.
Mentions: The families miR-23, miR-24, and miR-27 are organized in two clusters (Table 1). The cluster miR-23a~27a~24-2 is localized on chromosome 19 while cluster miR-23b~27b~24-1 is on chromosome 9 [4,6,35]. In cervical carcinoma cells it was shown that miR-23b diminished uPA expression via 3′-UTR mRNA binding [36] (Figure 3). This protein is a serine protease that degrades plasminogen to plasmin, thus activating metalloproteinases and inducing extracellular matrix (ECM) degradation. Recently it was shown that an increase of Notch receptors’ expression triggers the Notch pathway by uPA activation [37]. Additionally, JAG-Notch activation stimulates uPA transcription [38,39], inducing a mutual signaling activation exacerbated by miR-23b absence favoring cancer progression (Figure 3). The clusters miR-23a~27a~24-2 and 23b~27b~24-1 have a high similarity; however, it appears that the members of these clusters have opposite profile expressions: whereas miR-27a is upregulated, miR-23b and miR-27b are downregulated in cervical cancer [12]. MiR-23a, miR-27a, and miR-27b from the two clusters have sequences that may potentially regulate uPA (microRNA.org, MIRDB, and Target Scan). It remains to be addressed whether miRNAs of these clusters regulated the same targets to elucidate the participation of these clusters in cervical cancer’s advance.

Bottom Line: Individual miRNA expression is reported without considering that miRNAs are grouped in clusters and may have similar functions, such as the case of clusters with anti-oncomiRs (23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR-99a~125b-2, miR-99b~125a, miR-100~125b-1, miR-199a-2~214, and miR-302s) or oncomiRs activity (miR-1-1~133a-2, miR-1-2~133a-1, miR-133b~206, miR-17~92, miR-106a~363, miR183~96~182, miR-181a-1~181b-1, and miR-181a-2~181b-2), which regulated mitogen-activated protein kinases (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), NOTCH, proteasome-culling rings, and apoptosis cell signaling.In this work we point out the pathways regulated by families of miRNAs grouped in 20 clusters involved in cervical cancer.Reviewing how miRNA families expressed in cluster-regulated cell path signaling will increase the knowledge of cervical cancer progression, providing important information for therapeutic, diagnostic, and prognostic methodology design.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de microRNAs, Unidad Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas, Av. Preparatoria S/N, Zacatecas 98066, Mexico. stevenservin07@gmail.com.

ABSTRACT
Tumor cells have developed advantages to acquire hallmarks of cancer like apoptosis resistance, increased proliferation, migration, and invasion through cell signaling pathway misregulation. The sequential activation of genes in a pathway is regulated by miRNAs. Loss or gain of miRNA expression could activate or repress a particular cell axis. It is well known that aberrant miRNA expression is well recognized as an important step in the development of cancer. Individual miRNA expression is reported without considering that miRNAs are grouped in clusters and may have similar functions, such as the case of clusters with anti-oncomiRs (23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR-99a~125b-2, miR-99b~125a, miR-100~125b-1, miR-199a-2~214, and miR-302s) or oncomiRs activity (miR-1-1~133a-2, miR-1-2~133a-1, miR-133b~206, miR-17~92, miR-106a~363, miR183~96~182, miR-181a-1~181b-1, and miR-181a-2~181b-2), which regulated mitogen-activated protein kinases (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), NOTCH, proteasome-culling rings, and apoptosis cell signaling. In this work we point out the pathways regulated by families of miRNAs grouped in 20 clusters involved in cervical cancer. Reviewing how miRNA families expressed in cluster-regulated cell path signaling will increase the knowledge of cervical cancer progression, providing important information for therapeutic, diagnostic, and prognostic methodology design.

No MeSH data available.


Related in: MedlinePlus