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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 Bcl-12l2-Bax-CASPS, MST1-MEK-4/7-JNK-1-MSK2, MST1-MEK-3-p38-MSK1, PI3K-PDK1-AKT, and Ras-Raf-MEK1-ERK1/2 cell signaling by the miR-214~199a-2 cluster. The anti-oncomiR-214 from the cluster miR-214~199a-2 promotes apoptosis by downregulation of Bcl-12-l2, permitting Bax activation with a consequent activation of caspases 9, 8, and 3. Furthermore, miR-214 inhibits JNK1 and MEK3, participants of cell signaling MST1-MEK-4/7-JNK-1-MSK2 and MST1-MEK-3-p38-MSK1, respectively. In addition, miR-214 controls MAPK activation by the downregulation of Plexin-B1, which in contact with Sema 4D activates RhoA, which then activates Raf-1 triggering MEK-1 and ERK1/2 phosphorylation together with PI3K-PIP3-PDK1-AKT, promoting the hallmarks of cancer. In bold are the miRNAs with effect on genes with validated experimental data.
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ijms-16-12773-f005: Regulation of Bcl-12l2-Bax-CASPS, MST1-MEK-4/7-JNK-1-MSK2, MST1-MEK-3-p38-MSK1, PI3K-PDK1-AKT, and Ras-Raf-MEK1-ERK1/2 cell signaling by the miR-214~199a-2 cluster. The anti-oncomiR-214 from the cluster miR-214~199a-2 promotes apoptosis by downregulation of Bcl-12-l2, permitting Bax activation with a consequent activation of caspases 9, 8, and 3. Furthermore, miR-214 inhibits JNK1 and MEK3, participants of cell signaling MST1-MEK-4/7-JNK-1-MSK2 and MST1-MEK-3-p38-MSK1, respectively. In addition, miR-214 controls MAPK activation by the downregulation of Plexin-B1, which in contact with Sema 4D activates RhoA, which then activates Raf-1 triggering MEK-1 and ERK1/2 phosphorylation together with PI3K-PIP3-PDK1-AKT, promoting the hallmarks of cancer. In bold are the miRNAs with effect on genes with validated experimental data.

Mentions: Family miR-199 is formed of miR-199a-1, miR-199a-2, and miR-199b [6]. One member of family miR-199, miR-199a-2, is clustered with miR-214 [67,68] on chromosome 1, separated by 5628 nt [6] (Table 1). MiR-214 functions as anti-oncomiR in cervical cancer in this respect; it is not known if miR-199a-2 has the same role or if it participates in cellular pathways regulated by miR-214. The targets of miR-214 are implicated on several cellular pathways. For example, signaling through trans-membrane receptor Plexin-B1 induced cell survival, proliferation, angiogenesis, invasion, and metastasis in cervical cancer [69]. Semaphorin D4 binds to Plexin-B1, inducing the activation of RhoA, which in turn activates the Raf protein, triggering MEK/ERK signaling [20]. Cell-signaling pathway MEK/JNK is inhibited by miR-214 targeting MEK3 and JNK1, decreasing cell proliferation [70]. Importantly, these pathways have different targets. On one hand, MEK3 induces p38 activation by phosphorylation, resulting in MSK1 triggering. On the other hand, JNK1 activates MSK2 (Figure 5). Additionally, miR-214 reduces GALNT-7 protein expression, affecting proliferation, migration, and invasion in cervical cell lines [71], and controls cell death through mRNA and protein downregulation of anti-apoptotic proteins like Bcl-2l2, which in turn induces Bax increment and caspase 9, 8, and 3, the activation of which triggers intrinsic/extrinsic apoptosis pathways [72] (Figure 5).


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 Bcl-12l2-Bax-CASPS, MST1-MEK-4/7-JNK-1-MSK2, MST1-MEK-3-p38-MSK1, PI3K-PDK1-AKT, and Ras-Raf-MEK1-ERK1/2 cell signaling by the miR-214~199a-2 cluster. The anti-oncomiR-214 from the cluster miR-214~199a-2 promotes apoptosis by downregulation of Bcl-12-l2, permitting Bax activation with a consequent activation of caspases 9, 8, and 3. Furthermore, miR-214 inhibits JNK1 and MEK3, participants of cell signaling MST1-MEK-4/7-JNK-1-MSK2 and MST1-MEK-3-p38-MSK1, respectively. In addition, miR-214 controls MAPK activation by the downregulation of Plexin-B1, which in contact with Sema 4D activates RhoA, which then activates Raf-1 triggering MEK-1 and ERK1/2 phosphorylation together with PI3K-PIP3-PDK1-AKT, promoting the hallmarks of cancer. In bold are the miRNAs with effect on genes with validated experimental data.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-12773-f005: Regulation of Bcl-12l2-Bax-CASPS, MST1-MEK-4/7-JNK-1-MSK2, MST1-MEK-3-p38-MSK1, PI3K-PDK1-AKT, and Ras-Raf-MEK1-ERK1/2 cell signaling by the miR-214~199a-2 cluster. The anti-oncomiR-214 from the cluster miR-214~199a-2 promotes apoptosis by downregulation of Bcl-12-l2, permitting Bax activation with a consequent activation of caspases 9, 8, and 3. Furthermore, miR-214 inhibits JNK1 and MEK3, participants of cell signaling MST1-MEK-4/7-JNK-1-MSK2 and MST1-MEK-3-p38-MSK1, respectively. In addition, miR-214 controls MAPK activation by the downregulation of Plexin-B1, which in contact with Sema 4D activates RhoA, which then activates Raf-1 triggering MEK-1 and ERK1/2 phosphorylation together with PI3K-PIP3-PDK1-AKT, promoting the hallmarks of cancer. In bold are the miRNAs with effect on genes with validated experimental data.
Mentions: Family miR-199 is formed of miR-199a-1, miR-199a-2, and miR-199b [6]. One member of family miR-199, miR-199a-2, is clustered with miR-214 [67,68] on chromosome 1, separated by 5628 nt [6] (Table 1). MiR-214 functions as anti-oncomiR in cervical cancer in this respect; it is not known if miR-199a-2 has the same role or if it participates in cellular pathways regulated by miR-214. The targets of miR-214 are implicated on several cellular pathways. For example, signaling through trans-membrane receptor Plexin-B1 induced cell survival, proliferation, angiogenesis, invasion, and metastasis in cervical cancer [69]. Semaphorin D4 binds to Plexin-B1, inducing the activation of RhoA, which in turn activates the Raf protein, triggering MEK/ERK signaling [20]. Cell-signaling pathway MEK/JNK is inhibited by miR-214 targeting MEK3 and JNK1, decreasing cell proliferation [70]. Importantly, these pathways have different targets. On one hand, MEK3 induces p38 activation by phosphorylation, resulting in MSK1 triggering. On the other hand, JNK1 activates MSK2 (Figure 5). Additionally, miR-214 reduces GALNT-7 protein expression, affecting proliferation, migration, and invasion in cervical cell lines [71], and controls cell death through mRNA and protein downregulation of anti-apoptotic proteins like Bcl-2l2, which in turn induces Bax increment and caspase 9, 8, and 3, the activation of which triggers intrinsic/extrinsic apoptosis pathways [72] (Figure 5).

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