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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 MAPK, PI3K-AKT, and G2-M checkpoint by members of the family miR-125 and members of miR-let-7c~99a, miR-125a~let-7e~99b, miR-100~let-7a-2, and miR-206~133b clusters in cervical cancer. MAPK cell signaling is triggered by MEK-1 activation via TRIB2 and HOXA1 conducing to ERK1/2 phosphorylation, thereby provoking apoptosis reduction and inducing proliferation, migration, and invasion. This pathway is regulated by downregulation of TRIB2 and HOXA1 by the family miR-99 clustered in miR-let-7c~99a, miR-125a~let-7e~99b, and miR-100~let-7a-2. The members of these clusters are diminished in cervical cancer. MST2 inhibits Raf-1 and activates LAST2/YAP, reducing Ras-MEK-ERK activation, thus diminishing proliferation and inducing apoptosis, respectively. The oncomiR-133b from the cluster miR-133b~206 inhibits the tumor suppressor MST2. As well as CDC42 and RhoA that in turn inactivates Plexin B1 and PTEN increasing PI3K-PDK1-AKT-mTOR signaling, thus augmenting translation. MiR-125a from the cluster miR-125a~let-7e~99b counteracts the effect of miR-133b through the downregulation of PIK3CD, inhibiting PI3K-PDK1-AKT-mTOR signaling. The family miR-99 reduces mTOR protein expression, having an opposite effect to the miR-206~133b cluster. The cell cycle is arrested by DNA damage via ATM and ATR activation consecutively by the activation of Chk1/2 blocking CDC25 hampering CDK1 stopping transition from G2 to M. ATM and ATR prevent Bora activation conducing to Aurora A, PlK1 and MDM2 inactivation, thereby stabilizing p53 and activating miR-34 family transcription. Also, p53 is activated directly by Chk1/2, ATR, and ATM. In cervical cancer PlK1 is upregulated because miR-100 from the cluster miR-100~let-7a-2 is downregulated, promoting MDM2 increase and contributing to p53 decrease, with a concomitant miR-34 family shrink increasing protein translation, proliferation, and apoptosis reduction. In bold are the miRNAs with effect on genes with validated experimental data.
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ijms-16-12773-f001: Regulation of MAPK, PI3K-AKT, and G2-M checkpoint by members of the family miR-125 and members of miR-let-7c~99a, miR-125a~let-7e~99b, miR-100~let-7a-2, and miR-206~133b clusters in cervical cancer. MAPK cell signaling is triggered by MEK-1 activation via TRIB2 and HOXA1 conducing to ERK1/2 phosphorylation, thereby provoking apoptosis reduction and inducing proliferation, migration, and invasion. This pathway is regulated by downregulation of TRIB2 and HOXA1 by the family miR-99 clustered in miR-let-7c~99a, miR-125a~let-7e~99b, and miR-100~let-7a-2. The members of these clusters are diminished in cervical cancer. MST2 inhibits Raf-1 and activates LAST2/YAP, reducing Ras-MEK-ERK activation, thus diminishing proliferation and inducing apoptosis, respectively. The oncomiR-133b from the cluster miR-133b~206 inhibits the tumor suppressor MST2. As well as CDC42 and RhoA that in turn inactivates Plexin B1 and PTEN increasing PI3K-PDK1-AKT-mTOR signaling, thus augmenting translation. MiR-125a from the cluster miR-125a~let-7e~99b counteracts the effect of miR-133b through the downregulation of PIK3CD, inhibiting PI3K-PDK1-AKT-mTOR signaling. The family miR-99 reduces mTOR protein expression, having an opposite effect to the miR-206~133b cluster. The cell cycle is arrested by DNA damage via ATM and ATR activation consecutively by the activation of Chk1/2 blocking CDC25 hampering CDK1 stopping transition from G2 to M. ATM and ATR prevent Bora activation conducing to Aurora A, PlK1 and MDM2 inactivation, thereby stabilizing p53 and activating miR-34 family transcription. Also, p53 is activated directly by Chk1/2, ATR, and ATM. In cervical cancer PlK1 is upregulated because miR-100 from the cluster miR-100~let-7a-2 is downregulated, promoting MDM2 increase and contributing to p53 decrease, with a concomitant miR-34 family shrink increasing protein translation, proliferation, and apoptosis reduction. In bold are the miRNAs with effect on genes with validated experimental data.

Mentions: The cluster miR-133a-2~1-1 is formed by miR-1-1 and miR-133a-2 [11], localized on chromosome 20, having 10,536 nt of distance between them. In this sense miR-1-2 and miR-133a-1 could be expressed as a cluster since the distance between them is 3219 nt long and they are localized on chromosome 18. In a similar way, miR-133b and miR-206 are localized on chromosome 6 and the distance between them is 4607 nt long [6]. Interestingly, miR-1 and miR-133 from the clusters miR-133a-2~1-1 and miR1-2~133a-1 have opposite expression in cervical cancer: whereas miR-1 is downregulated, miR-133 is upregulated [12]. MiR-133b from the cluster miR-206~133b over-expression activates AKT1, ERK1, and ERK2 phosphorylation, inducing cell proliferation and colony formation in cervical cell lines by the degradation/inhibition of mRNAs and proteins of mammalian sterile 20-like kinase 2 (MST2), cell division control protein 42 homolog (CDC42), and Ras homolog gene family member A (RhoA) [13] (Figure 1). Proliferation and apoptosis are regulated through Raf-1 and MST2 activation. Raf-1 is activated by Ras inducing MEK1, ERK1, and ERK2 phosphorylation [14], while MST2 triggers apoptosis through PUMA and caspases activation. MST2–Raf-1 interaction inhibits MST2 activation while MST2-RASSF1A interaction activates MST2. RASSF1A and Raf-1 compete for binding sites within MST2 [14,15]. Apoptosis stimulus induces MST2-RASSF1A interaction, activating MST2. AKT phosphorylates MST2, inducing Raf-1 interaction and thereby releasing RASSF1A from the complex inducing MST2 inhibition [15]. Furthermore, RhoA and CDC42 inhibit ERK1/2 activation as well as AKT signaling through PTEN activation [16,17,18]; however, it should be noted that RhoA could activate the cell signaling PI3K/AKT and ERK1/2 by the activation of Plexin-B1 [19,20], and probably by CDC42 too (Figure 1). It seems that a cell-specific pathway axis activation or inactivation response is dependent on intensity and time [18]. The AKT and MAPK cell signaling pathways have an intricate and complex regulation to induce cancer that in part could be explained by miRNA family members’ misregulation. MiR-133a and miR-133b differ at a single 3′ terminal nt and have similar expression levels in cervical cancer [12]; therefore, it is possible that there is a similar type of regulation on AKT and MAPK signaling (Figure 1).


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 MAPK, PI3K-AKT, and G2-M checkpoint by members of the family miR-125 and members of miR-let-7c~99a, miR-125a~let-7e~99b, miR-100~let-7a-2, and miR-206~133b clusters in cervical cancer. MAPK cell signaling is triggered by MEK-1 activation via TRIB2 and HOXA1 conducing to ERK1/2 phosphorylation, thereby provoking apoptosis reduction and inducing proliferation, migration, and invasion. This pathway is regulated by downregulation of TRIB2 and HOXA1 by the family miR-99 clustered in miR-let-7c~99a, miR-125a~let-7e~99b, and miR-100~let-7a-2. The members of these clusters are diminished in cervical cancer. MST2 inhibits Raf-1 and activates LAST2/YAP, reducing Ras-MEK-ERK activation, thus diminishing proliferation and inducing apoptosis, respectively. The oncomiR-133b from the cluster miR-133b~206 inhibits the tumor suppressor MST2. As well as CDC42 and RhoA that in turn inactivates Plexin B1 and PTEN increasing PI3K-PDK1-AKT-mTOR signaling, thus augmenting translation. MiR-125a from the cluster miR-125a~let-7e~99b counteracts the effect of miR-133b through the downregulation of PIK3CD, inhibiting PI3K-PDK1-AKT-mTOR signaling. The family miR-99 reduces mTOR protein expression, having an opposite effect to the miR-206~133b cluster. The cell cycle is arrested by DNA damage via ATM and ATR activation consecutively by the activation of Chk1/2 blocking CDC25 hampering CDK1 stopping transition from G2 to M. ATM and ATR prevent Bora activation conducing to Aurora A, PlK1 and MDM2 inactivation, thereby stabilizing p53 and activating miR-34 family transcription. Also, p53 is activated directly by Chk1/2, ATR, and ATM. In cervical cancer PlK1 is upregulated because miR-100 from the cluster miR-100~let-7a-2 is downregulated, promoting MDM2 increase and contributing to p53 decrease, with a concomitant miR-34 family shrink increasing protein translation, proliferation, and apoptosis reduction. In bold are the miRNAs with effect on genes with validated experimental data.
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Related In: Results  -  Collection

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

ijms-16-12773-f001: Regulation of MAPK, PI3K-AKT, and G2-M checkpoint by members of the family miR-125 and members of miR-let-7c~99a, miR-125a~let-7e~99b, miR-100~let-7a-2, and miR-206~133b clusters in cervical cancer. MAPK cell signaling is triggered by MEK-1 activation via TRIB2 and HOXA1 conducing to ERK1/2 phosphorylation, thereby provoking apoptosis reduction and inducing proliferation, migration, and invasion. This pathway is regulated by downregulation of TRIB2 and HOXA1 by the family miR-99 clustered in miR-let-7c~99a, miR-125a~let-7e~99b, and miR-100~let-7a-2. The members of these clusters are diminished in cervical cancer. MST2 inhibits Raf-1 and activates LAST2/YAP, reducing Ras-MEK-ERK activation, thus diminishing proliferation and inducing apoptosis, respectively. The oncomiR-133b from the cluster miR-133b~206 inhibits the tumor suppressor MST2. As well as CDC42 and RhoA that in turn inactivates Plexin B1 and PTEN increasing PI3K-PDK1-AKT-mTOR signaling, thus augmenting translation. MiR-125a from the cluster miR-125a~let-7e~99b counteracts the effect of miR-133b through the downregulation of PIK3CD, inhibiting PI3K-PDK1-AKT-mTOR signaling. The family miR-99 reduces mTOR protein expression, having an opposite effect to the miR-206~133b cluster. The cell cycle is arrested by DNA damage via ATM and ATR activation consecutively by the activation of Chk1/2 blocking CDC25 hampering CDK1 stopping transition from G2 to M. ATM and ATR prevent Bora activation conducing to Aurora A, PlK1 and MDM2 inactivation, thereby stabilizing p53 and activating miR-34 family transcription. Also, p53 is activated directly by Chk1/2, ATR, and ATM. In cervical cancer PlK1 is upregulated because miR-100 from the cluster miR-100~let-7a-2 is downregulated, promoting MDM2 increase and contributing to p53 decrease, with a concomitant miR-34 family shrink increasing protein translation, proliferation, and apoptosis reduction. In bold are the miRNAs with effect on genes with validated experimental data.
Mentions: The cluster miR-133a-2~1-1 is formed by miR-1-1 and miR-133a-2 [11], localized on chromosome 20, having 10,536 nt of distance between them. In this sense miR-1-2 and miR-133a-1 could be expressed as a cluster since the distance between them is 3219 nt long and they are localized on chromosome 18. In a similar way, miR-133b and miR-206 are localized on chromosome 6 and the distance between them is 4607 nt long [6]. Interestingly, miR-1 and miR-133 from the clusters miR-133a-2~1-1 and miR1-2~133a-1 have opposite expression in cervical cancer: whereas miR-1 is downregulated, miR-133 is upregulated [12]. MiR-133b from the cluster miR-206~133b over-expression activates AKT1, ERK1, and ERK2 phosphorylation, inducing cell proliferation and colony formation in cervical cell lines by the degradation/inhibition of mRNAs and proteins of mammalian sterile 20-like kinase 2 (MST2), cell division control protein 42 homolog (CDC42), and Ras homolog gene family member A (RhoA) [13] (Figure 1). Proliferation and apoptosis are regulated through Raf-1 and MST2 activation. Raf-1 is activated by Ras inducing MEK1, ERK1, and ERK2 phosphorylation [14], while MST2 triggers apoptosis through PUMA and caspases activation. MST2–Raf-1 interaction inhibits MST2 activation while MST2-RASSF1A interaction activates MST2. RASSF1A and Raf-1 compete for binding sites within MST2 [14,15]. Apoptosis stimulus induces MST2-RASSF1A interaction, activating MST2. AKT phosphorylates MST2, inducing Raf-1 interaction and thereby releasing RASSF1A from the complex inducing MST2 inhibition [15]. Furthermore, RhoA and CDC42 inhibit ERK1/2 activation as well as AKT signaling through PTEN activation [16,17,18]; however, it should be noted that RhoA could activate the cell signaling PI3K/AKT and ERK1/2 by the activation of Plexin-B1 [19,20], and probably by CDC42 too (Figure 1). It seems that a cell-specific pathway axis activation or inactivation response is dependent on intensity and time [18]. The AKT and MAPK cell signaling pathways have an intricate and complex regulation to induce cancer that in part could be explained by miRNA family members’ misregulation. MiR-133a and miR-133b differ at a single 3′ terminal nt and have similar expression levels in cervical cancer [12]; therefore, it is possible that there is a similar type of regulation on AKT and MAPK signaling (Figure 1).

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