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AurkA controls self-renewal of breast cancer-initiating cells promoting wnt3a stabilization through suppression of miR-128.

Eterno V, Zambelli A, Villani L, Tuscano A, Manera S, Spitaleri A, Pavesi L, Amato A - Sci Rep (2016)

Bottom Line: In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells.As a consequence, the amount of BCICs and their migratory capability dramatically decreased.In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

View Article: PubMed Central - PubMed

Affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.

ABSTRACT
AurkA overexpression was previously found in breast cancer and associated to its ability in controlling chromosome segregation during mitosis, however whether it may affect breast cancer cells, endorsed with stem properties (BCICs), is still unclear. Surprisingly, a strong correlation between AurkA expression and β-catenin localization in breast cancer tissues suggested a link between AurkA and Wnt signaling. In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells. As a consequence, the amount of BCICs and their migratory capability dramatically decreased. Conversely, wnt3a mRNA stabilization and increased CD44(+)/CD24(low/-) subpopulation was found in AurkA-overexpressing MCF7 cells. In vivo, AurkA-overexpressing primary breast cancer cells showed higher tumorigenic properties. Interestingly, we found that AurkA suppressed the expression of miR-128, inhibitor of wnt3a mRNA stabilization. Namely, miR-128 suppression realized after AurkA binding to Snail. Remarkably, a strong correlation between AurkA and miR-128 expression in breast cancer tissues confirmed our findings. This study provides novel insights into an undisclosed role for the kinase AurkA in self-renewal and migration of BCICs affecting response to cancer therapies, metastatic spread and recurrence. In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

No MeSH data available.


Related in: MedlinePlus

Aurka controls breast cancer stem cells through regulation of Wnt/β-catenin.(A) AurkA overexpression in MCF-7 cells promoted AurkA protein stabilization and increased levels of β–catenin, Wnt3a, Stat3 and Mmp9 proteins; (B) conversely, AurkA knock-down dramatically reduced AurkA protein levels as well as levels of β–catenin, Wnt3a, Stat3 and Mmp9 proteins. β–actin is a loading control. (C) AurkA overexpression associated with a metastatic signature in MCF-AurkA cells as suggested by increased expression of CD44v6, Snail, Twist and c-Met and increased migratory activity (right graph) in comparison with control cells (empty). (D) In contrast, MDA-shAurkA cells lost that signature showing a repression of CD44v6, Snail and c-Met and a marked inhibition of migratory activity (right graph) in comparison with control cells (empty).
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f3: Aurka controls breast cancer stem cells through regulation of Wnt/β-catenin.(A) AurkA overexpression in MCF-7 cells promoted AurkA protein stabilization and increased levels of β–catenin, Wnt3a, Stat3 and Mmp9 proteins; (B) conversely, AurkA knock-down dramatically reduced AurkA protein levels as well as levels of β–catenin, Wnt3a, Stat3 and Mmp9 proteins. β–actin is a loading control. (C) AurkA overexpression associated with a metastatic signature in MCF-AurkA cells as suggested by increased expression of CD44v6, Snail, Twist and c-Met and increased migratory activity (right graph) in comparison with control cells (empty). (D) In contrast, MDA-shAurkA cells lost that signature showing a repression of CD44v6, Snail and c-Met and a marked inhibition of migratory activity (right graph) in comparison with control cells (empty).

Mentions: The involvement of AurkA in regulation of BCICs was further confirmed by western blot analysis showing increased wnt3a and β-catenin in MCF-AurkA cells (Fig. 3A). Conversely β-catenin degradation and undetectable wnt3a levels were found in MDA-shAurkA (Fig. 3B). Those data strongly suggested that the kinase may control BCICs through the Wnt3a/β-catenin axis.


AurkA controls self-renewal of breast cancer-initiating cells promoting wnt3a stabilization through suppression of miR-128.

Eterno V, Zambelli A, Villani L, Tuscano A, Manera S, Spitaleri A, Pavesi L, Amato A - Sci Rep (2016)

Aurka controls breast cancer stem cells through regulation of Wnt/β-catenin.(A) AurkA overexpression in MCF-7 cells promoted AurkA protein stabilization and increased levels of β–catenin, Wnt3a, Stat3 and Mmp9 proteins; (B) conversely, AurkA knock-down dramatically reduced AurkA protein levels as well as levels of β–catenin, Wnt3a, Stat3 and Mmp9 proteins. β–actin is a loading control. (C) AurkA overexpression associated with a metastatic signature in MCF-AurkA cells as suggested by increased expression of CD44v6, Snail, Twist and c-Met and increased migratory activity (right graph) in comparison with control cells (empty). (D) In contrast, MDA-shAurkA cells lost that signature showing a repression of CD44v6, Snail and c-Met and a marked inhibition of migratory activity (right graph) in comparison with control cells (empty).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920028&req=5

f3: Aurka controls breast cancer stem cells through regulation of Wnt/β-catenin.(A) AurkA overexpression in MCF-7 cells promoted AurkA protein stabilization and increased levels of β–catenin, Wnt3a, Stat3 and Mmp9 proteins; (B) conversely, AurkA knock-down dramatically reduced AurkA protein levels as well as levels of β–catenin, Wnt3a, Stat3 and Mmp9 proteins. β–actin is a loading control. (C) AurkA overexpression associated with a metastatic signature in MCF-AurkA cells as suggested by increased expression of CD44v6, Snail, Twist and c-Met and increased migratory activity (right graph) in comparison with control cells (empty). (D) In contrast, MDA-shAurkA cells lost that signature showing a repression of CD44v6, Snail and c-Met and a marked inhibition of migratory activity (right graph) in comparison with control cells (empty).
Mentions: The involvement of AurkA in regulation of BCICs was further confirmed by western blot analysis showing increased wnt3a and β-catenin in MCF-AurkA cells (Fig. 3A). Conversely β-catenin degradation and undetectable wnt3a levels were found in MDA-shAurkA (Fig. 3B). Those data strongly suggested that the kinase may control BCICs through the Wnt3a/β-catenin axis.

Bottom Line: In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells.As a consequence, the amount of BCICs and their migratory capability dramatically decreased.In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

View Article: PubMed Central - PubMed

Affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.

ABSTRACT
AurkA overexpression was previously found in breast cancer and associated to its ability in controlling chromosome segregation during mitosis, however whether it may affect breast cancer cells, endorsed with stem properties (BCICs), is still unclear. Surprisingly, a strong correlation between AurkA expression and β-catenin localization in breast cancer tissues suggested a link between AurkA and Wnt signaling. In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells. As a consequence, the amount of BCICs and their migratory capability dramatically decreased. Conversely, wnt3a mRNA stabilization and increased CD44(+)/CD24(low/-) subpopulation was found in AurkA-overexpressing MCF7 cells. In vivo, AurkA-overexpressing primary breast cancer cells showed higher tumorigenic properties. Interestingly, we found that AurkA suppressed the expression of miR-128, inhibitor of wnt3a mRNA stabilization. Namely, miR-128 suppression realized after AurkA binding to Snail. Remarkably, a strong correlation between AurkA and miR-128 expression in breast cancer tissues confirmed our findings. This study provides novel insights into an undisclosed role for the kinase AurkA in self-renewal and migration of BCICs affecting response to cancer therapies, metastatic spread and recurrence. In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

No MeSH data available.


Related in: MedlinePlus