Down-Regulation of mir-424 Contributes to the Abnormal Angiogenesis via MEK1 and Cyclin E1 in Senile Hemangioma: Its Implications to Therapy

Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
PLoS ONE (Impact Factor: 3.23). 12/2010; 5(12):e14334. DOI: 10.1371/journal.pone.0014334
Source: PubMed


Senile hemangioma, so-called cherry angioma, is known as the most common vascular anomalies specifically seen in the aged skin. The pathogenesis of its abnormal angiogenesis is still unclear.
In this study, we found that senile hemangioma consisted of clusters of proliferated small vascular channels in upper dermis, indicating that this tumor is categorized as a vascular tumor. We then investigated the mechanism of endothelial proliferation in senile hemangioma, focusing on microRNA (miRNA). miRNA PCR array analysis revealed the mir-424 level in senile hemangioma was lower than in other vascular anomalies. Protein expression of MEK1 and cyclin E1, the predicted target genes of mir-424, was increased in senile hemangioma compared to normal skin or other anomalies, but their mRNA levels were not. The inhibition of mir-424 in normal human dermal microvascular ECs (HDMECs) using specific inhibitor in vitro resulted in the increase of protein expression of MEK1 or cyclin E1, while mRNA levels were not affected by the inhibitor. Specific inhibitor of mir-424 also induced the cell proliferation of HDMECs significantly, while the cell number was decreased by the transfection of siRNA for MEK1 or cyclin E1.
Taken together, decreased mir-424 expression and increased levels of MEK1 or cyclin E1 in senile hemangioma may cause abnormal cell proliferation in the tumor. Senile hemangioma may be the good model for cutaneous angiogenesis. Investigation of senile hemangioma and the regulatory mechanisms of angiogenesis by miRNA in the aged skin may lead to new treatments using miRNA by the transfection into senile hemangioma.

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Available from: Hironobu Ihn,
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    • "Previous studies have shown that miR-424 may act as a potential suppressor miRNA [23], [24]. For example, miR-424 was down-regulated in cervical cancer tissues and correlated with progression of the cervical cancer [25]. "
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    • "miR-424, one of the miR-16/15/195/424/497 family members, induces muscle differentiation and promotes cell cycle quiescence and differentiation (27–29) and regulates cell-autonomous angiogenesis (30–32). Recent evidence demonstrated that miR-424 plays an important role in tumorigenesis (33–34). "
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    • "Furthermore, the mouse hind limb ischemia model and myocardial infarction model demonstrated that antagomir-92a led to enhanced growth of blood vessels and functional recovery of damaged tissue. Moreover, miR-210 [49], miR-221 [50], miR-222 [51], miR-100 [44], miR-424 [52] and miR-503 [53] have also been shown to play critical roles in the modulation of angiogenesis (Table 1). "
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