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An In Vitro Model for Studying Cellular Transformation by Kaposi Sarcoma Herpesvirus
Published on: August 25, 2017
MiR99a modulates MMP7 and MMP13 to regulate invasiveness of Kaposi's sarcoma
Abstract:
Matrix metalloproteinases (MMPs) and microRNAs (miRNAs) are associated with Kaposi's sarcoma (KS) tumorigenesis. To date, the molecular basis underlying crosstalk of MMPs and miRNAs in KS remains unexplored. From the resected KS samples, we detected significant correlation of miRNA99a (miR99a), with MMP7 and MMP13, but not with MMP9. To define whether a causal link exists, we used a human KS line, SLK, to study the molecular basis of miR99a and activation of MMP7, MMP9, and MMP13. We found that overexpression of miR99a in SLK cells decreased MMP7 and MMP13, but not MMP9. Similarly, MiR99a inhibition in SLK cells activated MMP7 and MMP13, but did not affect expression of MMP9. These data suggest that MMP7 and MMP13 seem to be regulated by miR99a, while MMP9 seems to be regulated in a miR99a-independent manner. Inhibition of PI3k/Akt signaling pathway significantly abolished the effect of miR99a-knockdown on MMP7, but not MMP13 activation, while inhibition of ERK/MAPK signaling pathway significantly abolished the effect of miR99a-knockdown on MMP13, but not MMP7 activation. Taken together, our data suggest that miR99a inhibits MMP7 and MMP13 through PI3k/Akt and ERK/MAPK signaling pathway, respectively, in KS. Thus, miR99a, MMP7, and MMP13 appear to be promising therapeutic targets for preventing the metastasis of KS.
Insights
MicroRNA 99a (miR99a) regulates matrix metalloproteinases (MMPs) MMP7 and MMP13 in Kaposi's sarcoma (KS) via PI3k/Akt and ERK/MAPK pathways, suggesting therapeutic potential for KS metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) and microRNAs (miRNAs) are implicated in Kaposi's sarcoma (KS) development.
- The molecular interactions between MMPs and miRNAs in KS are not well understood.
Purpose of the Study:
- To investigate the regulatory relationship between miRNA99a (miR99a) and MMPs (MMP7, MMP9, MMP13) in Kaposi's sarcoma.
- To elucidate the signaling pathways involved in miR99a-mediated regulation of MMPs in KS.
Main Methods:
- Correlation analysis of miR99a, MMP7, MMP13, and MMP9 in patient-derived KS samples.
- In vitro studies using a human KS cell line (SLK) to assess the effects of miR99a overexpression and inhibition on MMP expression.
- Pharmacological inhibition of PI3k/Akt and ERK/MAPK signaling pathways.
Main Results:
- miR99a expression correlated with MMP7 and MMP13, but not MMP9, in KS tissues.
- Overexpression of miR99a decreased MMP7 and MMP13, while inhibition increased their expression in SLK cells.
- MMP7 regulation by miR99a involved the PI3k/Akt pathway; MMP13 regulation involved the ERK/MAPK pathway.
- MMP9 expression was independent of miR99a regulation.
Conclusions:
- miR99a inhibits MMP7 and MMP13 expression in KS through distinct signaling pathways (PI3k/Akt and ERK/MAPK, respectively).
- MMP7 and MMP13, regulated by miR99a, are potential therapeutic targets to prevent KS metastasis.
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