Research Papers:

Angiogenin contributes to bladder cancer tumorigenesis by DNMT3b-mediated MMP2 activation

Rafael Peres _, Hideki Furuya, Ian Pagano, Yoshiko Shimizu, Kanani Hokutan and Charles J. Rosser

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Oncotarget. 2016; 7:43109-43123. https://doi.org/10.18632/oncotarget.10097

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Rafael Peres1, Hideki Furuya1, Ian Pagano2, Yoshiko Shimizu1,3, Kanani Hokutan1,3 and Charles J. Rosser1

1 University of Hawaii Cancer Center, Clinical & Translational Research Program, Honolulu, HI, USA

2 University of Hawaii Cancer Center, Cancer Prevention and Control Program, Honolulu, HI, USA

3 Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA

Correspondence to:

Charles J. Rosser, email:

Keywords: angiogenin, bladder cancer, DNMT3b, MMP2

Received: April 19, 2016 Accepted: May 14, 2016 Published: June 15, 2016


Epigenetic-mediated gene activation/silencing plays a crucial role in human tumorigenesis. Eliciting the underlying mechanism behind certain epigenetic changes is essential for understanding tumor biology. Previous studies in human cancers revealed an unrecognized interplay between Angiogenin (ANG) and matrix metalloproteinase-2 (MMP2) leading to pronounced tumorigenesis. Here we provide multiple lines of evidence further indicating ANG oncogenic potential. ANG expression resulted in the hypomethylated state of the MMP2 gene, which led to increased gene expression of MMP2. More than that, our global DNA methylation microarray analysis showed that gene manipulation of ANG affected a variety of pathways, such as cell migration, angiogenesis and specifically, tumor suppressor genes. Mechanistically, ANG negatively regulated DNA methyltransferase 3b (DNMT3b) enzymatic activity by down-regulating its expression and inhibiting its recruitment to the MMP2 promoter. Consistent with this, ANG-MMP2 overexpression and DNMT3b underexpression correlated with reduction in disease free survival of human bladder cancer patients. Together, the results continue to establish ANG as an oncoprotein and further reveal that ANG contributes to oncogenesis by the activation of MMP2 through modulation of DNMT3b functions.

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