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The role of wnt/β‐catenin signaling in regulating angiogenesis in hepatocellular carcinoma
Author(s) -
Delgado Evan R,
Bahal Raman,
Ly Danith,
Monga Satdarshan P. S.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.471.1
Subject(s) - angiogenesis , catenin , wnt signaling pathway , cancer research , transfection , biology , cyclin d1 , cell growth , microbiology and biotechnology , chemistry , cell culture , cell , signal transduction , cell cycle , biochemistry , genetics
Hepatocellular carcinoma (HCC) is the third cause of death by cancer worldwide. Activating β‐catenin gene mutations are observed in 30% of HCC and with its role in tumor cell survival and proliferation, β‐catenin is an attractive therapeutic target. However, its role in regulating angiogenesis in HCC remains obscure. Here, we characterize the role of β‐catenin in regulating angiogenesis and address its effect on endothelial cells. S33Y‐mutant but not wild‐type (WT) β‐catenin transfection in Huh7 and Hep3B cells resulted in increased expression of pro‐angiogenic secreted factors such as VEGF‐A. Concomitantly, we used a novel, cell permeable gamma guanidine‐based peptide nucleic acid (γGPNA) antisense oligonucleotide designed against the transcription start site (T1) of the human β‐catenin gene. Using TOPflash luciferase reporter assay, we show that γGPNA decreases Wnt/β‐catenin activity in HCC cells harboring activating β‐catenin mutations (HepG2 & Snu‐449). qRT‐PCR confirmed suppression of β‐catenin and western blot showed decreased protein expression of β‐catenin targets including glutamine synthetase (GS), cyclin‐D1, and VEGF‐A. Angiogenesis qRT‐PCR array also identified downregulation of several pro‐angiogenic secreted factors such as EphrinA1, FGF‐2, and VEGF‐A upon β‐ catenin inhibition. Conditioned media from γGPNA treated HepG2s was sufficient to reduce spheroid and tube formation by HCC‐associated endothelial cells (SK‐Hep1). Thus, our study shows an important role of β‐catenin in angiogenesis and validates it to be a major therapeutic target due to its roles in tumor cell viability, proliferation, metabolism and now in angiogenesis.