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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 CUL5, JAG-NOTCH, TNKS2, and PTEN-PI3K-AKT cell signaling by members of miR-17~92 and miR-106a~363 clusters in cervical cancer. E3 ubiquitin ligase complexes formed by CUL5-E2-SOCS-JAK2/3 and CUL1-skp1-skip2-E47-E2 are activated by Abs2 and SOCS interchange potentiated through JAG1-NOTCH axis. The cell signaling of GS3K-catenin-APC-AXIN-1-TCF/LEF is activated by AXIN-1 inhibition, which triggers the JAG1-NOTCH pathway, which in turn accelerates the interchange of SOCS by Abs2. Additionally, CUL1-skp1-skip2-E47-E2 is activated by phosphorylation of E47 via Ras-Raf-MEK-1-ERK1/2. The miR-19a and miR-19b grouped in the clusters miR17~92 and miR106a~363 downregulated CUL5, increasing proliferation, migration, and invasion and diminishing apoptosis. MiR-20a, a member of the cluster miR17~92, increases TNK2 expression that in turn inhibits AXIN-1, activating TCF/LEF, inducing JAG1-NOTCH1 signaling. Another member of the clusters miR17~92 and miR106a~363, miR-92, hinders PTEN expression, supporting PI3K-PDK1-AKT1 signaling thereby spreading proliferation, migration, invasion, and constraining apoptosis. In bold are the miRNAs with effect on genes with validated experimental data.
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ijms-16-12773-f002: Regulation of CUL5, JAG-NOTCH, TNKS2, and PTEN-PI3K-AKT cell signaling by members of miR-17~92 and miR-106a~363 clusters in cervical cancer. E3 ubiquitin ligase complexes formed by CUL5-E2-SOCS-JAK2/3 and CUL1-skp1-skip2-E47-E2 are activated by Abs2 and SOCS interchange potentiated through JAG1-NOTCH axis. The cell signaling of GS3K-catenin-APC-AXIN-1-TCF/LEF is activated by AXIN-1 inhibition, which triggers the JAG1-NOTCH pathway, which in turn accelerates the interchange of SOCS by Abs2. Additionally, CUL1-skp1-skip2-E47-E2 is activated by phosphorylation of E47 via Ras-Raf-MEK-1-ERK1/2. The miR-19a and miR-19b grouped in the clusters miR17~92 and miR106a~363 downregulated CUL5, increasing proliferation, migration, and invasion and diminishing apoptosis. MiR-20a, a member of the cluster miR17~92, increases TNK2 expression that in turn inhibits AXIN-1, activating TCF/LEF, inducing JAG1-NOTCH1 signaling. Another member of the clusters miR17~92 and miR106a~363, miR-92, hinders PTEN expression, supporting PI3K-PDK1-AKT1 signaling thereby spreading proliferation, migration, invasion, and constraining apoptosis. In bold are the miRNAs with effect on genes with validated experimental data.

Mentions: Xu et al. [22] showed that miR-19a/b from the cluster miR17~92 downregulates cullin 5 (CUL5) at the mRNA and protein level (Figure 2). CUL5 is a scaffold protein in E3 ubiquitin ligase complexes, which targets substrates for ubiquitin-dependent proteasome-mediated degradation [23]. The cullin-ring ligases form a bridge with the substrate-binding cytokine-inducible suppressors of cytokine signaling (SOCS) adaptor proteins and the E2 ubiquitin-conjugating enzyme [24]. Notch transcriptional signaling substitutes SOCS for ankyrin repeat and SOCS box-containing (Asb2) from the cullin-based complex constituted by S-phase kinase-associated protein 1 (skp1), skp2, CUL5, CUL1, E47, and E2 (Figure 2), inducing ubiquitination of its targets, which could be involved in differentiation and proliferation [25,26]. MAPK signaling is needed for E47 degradation [27] (Figure 2). A dual effect of these cell-signaling pathways is possible in cancer development: on one hand a turn-on of systems that favor tumor properties by phosphorylation, and on the other hand inducing ubiquitination-degradation of tumor suppressor genes by regulation of specific proteins of the ubiquitination-degradation system.


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 CUL5, JAG-NOTCH, TNKS2, and PTEN-PI3K-AKT cell signaling by members of miR-17~92 and miR-106a~363 clusters in cervical cancer. E3 ubiquitin ligase complexes formed by CUL5-E2-SOCS-JAK2/3 and CUL1-skp1-skip2-E47-E2 are activated by Abs2 and SOCS interchange potentiated through JAG1-NOTCH axis. The cell signaling of GS3K-catenin-APC-AXIN-1-TCF/LEF is activated by AXIN-1 inhibition, which triggers the JAG1-NOTCH pathway, which in turn accelerates the interchange of SOCS by Abs2. Additionally, CUL1-skp1-skip2-E47-E2 is activated by phosphorylation of E47 via Ras-Raf-MEK-1-ERK1/2. The miR-19a and miR-19b grouped in the clusters miR17~92 and miR106a~363 downregulated CUL5, increasing proliferation, migration, and invasion and diminishing apoptosis. MiR-20a, a member of the cluster miR17~92, increases TNK2 expression that in turn inhibits AXIN-1, activating TCF/LEF, inducing JAG1-NOTCH1 signaling. Another member of the clusters miR17~92 and miR106a~363, miR-92, hinders PTEN expression, supporting PI3K-PDK1-AKT1 signaling thereby spreading proliferation, migration, invasion, and constraining apoptosis. 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-f002: Regulation of CUL5, JAG-NOTCH, TNKS2, and PTEN-PI3K-AKT cell signaling by members of miR-17~92 and miR-106a~363 clusters in cervical cancer. E3 ubiquitin ligase complexes formed by CUL5-E2-SOCS-JAK2/3 and CUL1-skp1-skip2-E47-E2 are activated by Abs2 and SOCS interchange potentiated through JAG1-NOTCH axis. The cell signaling of GS3K-catenin-APC-AXIN-1-TCF/LEF is activated by AXIN-1 inhibition, which triggers the JAG1-NOTCH pathway, which in turn accelerates the interchange of SOCS by Abs2. Additionally, CUL1-skp1-skip2-E47-E2 is activated by phosphorylation of E47 via Ras-Raf-MEK-1-ERK1/2. The miR-19a and miR-19b grouped in the clusters miR17~92 and miR106a~363 downregulated CUL5, increasing proliferation, migration, and invasion and diminishing apoptosis. MiR-20a, a member of the cluster miR17~92, increases TNK2 expression that in turn inhibits AXIN-1, activating TCF/LEF, inducing JAG1-NOTCH1 signaling. Another member of the clusters miR17~92 and miR106a~363, miR-92, hinders PTEN expression, supporting PI3K-PDK1-AKT1 signaling thereby spreading proliferation, migration, invasion, and constraining apoptosis. In bold are the miRNAs with effect on genes with validated experimental data.
Mentions: Xu et al. [22] showed that miR-19a/b from the cluster miR17~92 downregulates cullin 5 (CUL5) at the mRNA and protein level (Figure 2). CUL5 is a scaffold protein in E3 ubiquitin ligase complexes, which targets substrates for ubiquitin-dependent proteasome-mediated degradation [23]. The cullin-ring ligases form a bridge with the substrate-binding cytokine-inducible suppressors of cytokine signaling (SOCS) adaptor proteins and the E2 ubiquitin-conjugating enzyme [24]. Notch transcriptional signaling substitutes SOCS for ankyrin repeat and SOCS box-containing (Asb2) from the cullin-based complex constituted by S-phase kinase-associated protein 1 (skp1), skp2, CUL5, CUL1, E47, and E2 (Figure 2), inducing ubiquitination of its targets, which could be involved in differentiation and proliferation [25,26]. MAPK signaling is needed for E47 degradation [27] (Figure 2). A dual effect of these cell-signaling pathways is possible in cancer development: on one hand a turn-on of systems that favor tumor properties by phosphorylation, and on the other hand inducing ubiquitination-degradation of tumor suppressor genes by regulation of specific proteins of the ubiquitination-degradation system.

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